Podcasts about Ionis

This CME program provides information on best practices to manage children with lysosomal disorders who have been identified by newborn screening. WIth the wide range of symptoms and severities that present for these rare conditions, it is not always certain when the best time to start treatment is in these patients.Continuing Education InformationThis continuing education activity is provided by AffinityCE and the Lysosomal and Rare Disorders Research and Treatment Center (LDRTC). This activity provides continuing education credit for physicians. A statement of participation is available to other attendees.To obtain credit, visit https://checkrare.com/learning/p-transforming-clinical-outcomes-with-early-treatment-of-lysosomal-disorders/ Faculty and DisclosuresAffinityCE staff, LDRTC staff, planners, and reviewers, have no relevant financial relationships with ineligible companies to disclose. Faculty disclosures, listed below, will also be disclosed at the beginning of the Program.Ozlem Goker-Alpan MDFounder and CMO, Lysosomal & Rare Disorders Research & Treatment CentersDr. Goker-Alpan is on the Advisory Board/Consultant for Chiesi, Takeda, Sanofi, Prevail/Lilly, Sparks Therapeutics, Uniqure, Exegenesis, Astellas, Freeline, Team Sanfilippo. She receives grants/research support from Chiesi, Sanofi, Takeda, Prevail/Lilly, Spark Therapeutics, Amicus, Freeline, Sangamo, Cyclo, Odorsia, DMT, Homology, Protaliz. She is on the speaker bureau for Sanofi, Takeda, Amicus, ChiesiDavid F. Kronn MDAssociate Professor of Pathology and Pediatrics                                                New York Medical CollegeDr. Kronn is on the Advisory Board for Sanofi. He is also on the speaker bureau for Sanofi. He receives research funding from Sanofi.Uma Ramaswami FRCPCH, MDRoyal Free London Hospitals & Genetics and Genomic Medicine, University College LondonDr. Ramaswami is on the Advisory Board for Amicus, Chiesi, Sanofi and Takeda. She receives research grants from Chiesi and Intabio.Liz Jalazo MDAssistant Professor of Pediatrics and GeneticsUniversity of North Carolina at Chapel HillDr. Jalazo is on the Advisory Board for Sanofi and Ionis. Lindsay Torrice MSN, CPNP-PC MDAssistant Professor of PediatricsUniversity of North Carolina at Chapel HillMs. Torrice has no financial relationships to disclose.Mitigation of Relevant Financial RelationshipsAffinityCE adheres to the ACCME's Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CME activity, including faculty, planners, reviewers, or others, are required to disclose all relevant financial relationships with ineligible companies. All relevant financial relationships for faculty were mitigated by the peer review of content by non-conflicted reviewers before the commencement of the activity.Learning ObjectivesAt the end of this activity, participants should be able to:•     Cite the importance of early diagnosis and treatment of lysosomal storage disorders•     List the guidelines for the early treatment of LDs and enhanced integration of newborn screening programs•     Identify key research gaps and priorities and strengthen collaboration among researchers and healthcare professionals•     List the educational resources and support programs for familiesPhysiciansThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of AffinityCE and the LDRTC. AffinityCE is accredited by the ACCME to provide continuing medical education for physicians.AffinityCE designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Other ProfessionalsAll other healthcare professionals completing this continuing education activity will be issued a statement of participation indicating the number of hours of continuing education credit. This may be used for professional education CE credit. Please consult your accrediting organization or licensing board for their acceptance of this CE activity.Commercial SupportThis activity was supported by educational grants from Takeda, Sanofi, and Chiesi.Participation CostsThere is no cost to participate in this activity. CME InquiriesFor all CME policy-related inquiries, please contact us at ce@affinityced.com.Send customer support requests to cds_support+ldrtc@affinityced.com.

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.AstraZeneca has recently made a significant investment of up to $1 billion in cell therapy through the acquisition of esobiotec. This move is part of AstraZeneca's larger strategy to expand in the cell therapy space, positioning itself to be a major player in the market. Dyne is also looking to file for accelerated approval for its Duchenne exon skipping oligomer, while Taiho Pharmaceutical has acquired ADC partner Araris for up to $1.1 billion. Alnylam is expected to enter the transthyretin amyloid cardiomyopathy market, which is projected to reach $11.2 billion by 2030.Sino Biological has developed reagents for the 2025-2026 influenza vaccine strains, offering a range of recombinant proteins for vaccine development. The pharmaceutical industry is seeing significant activity in various therapy areas, with companies making strategic investments and advancements in research and development.Alnylam is awaiting approval for their drug Amvuttra in the transthyretin amyloid cardiomyopathy market, which is currently dominated by Pfizer and BridgeBio. The obesity drug market is becoming increasingly competitive, with companies focusing on overall health benefits rather than just weight loss. Biopharma companies are now exploring the use of CAR T cell therapies for autoimmune disorders, with several readouts expected this year. Ionis and Ultragenyx are competing to develop treatments for Angelman syndrome, while Neuren is trying to catch up.Overall health outcomes are becoming more important in the obesity drug market, with successful studies in therapeutic areas like cardiovascular and sleep apnea providing a market advantage. Other news includes flu vaccine recommendations from the FDA and updates on drugs for alcohol use disorder, plaque psoriasis, breast cancer, and weight loss. The biopharma industry continues to evolve, with readers encouraged to provide suggestions for future coverage topics.

Hereditary angioedema (HAE) is a rare condition often due to reduced levels C1-inhibitor, which is a protein involved in various physiological processes in plasma, most notably with the complement system. C1-inhibitor also binds and inhibits plasma kallikrein and factor XIa, thereby affecting bradykinin production. It is believed that the disruptions of these processes cause fluid to leak from the blood to connective tissue, leading to HAE attacks. Owing to its rarity, HAE is often poorly recognized, leading to misdiagnoses and significant diagnostic delays. Being aware of the early signs and symptoms of this condition can lead to faster diagnosis and the use of effective therapies.This program is supported by independent medical education grants from Takeda. To earn CME credit please visit https://checkrare.com/learning/p-consider-rare-suspecting-and-diagnosing-hereditary-angioedema/lessons/consider-rare-suspecting-and-diagnosing-hereditary-angioedema-module/  Target AudienceThis activity has been designed to meet the educational needs of physicians specializing in primary care, pediatrics, emergency care, otolaryngology, gastroenterology, and dermatology .Other members of the care team may also participate.Learning ObjectivesAfter participating in the activity, learners should be better able to:- Describe the early symptoms of HAE and its clinical relevance.- Apply best practices to diagnose HAE more efficiently to reduce diagnostic delays. Faculty Jonathan A Bernstein, MDProfessor of MedicineUniversity of Cincinnati Department of Internal MedicineDivision of Immunology, Allergy SectionPartner Advanced Allergy Services, LLCPartner Bernstein Clinical Research Center Disclosure StatementAccording to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relationships with any ineligible company(ies). The existence of these relationships is not viewed as implying bias or decreasing the value of the activity. Clinical content has been reviewed for fair balance and scientific objectivity, and all of the relevant financial relationships listed for these individuals have been mitigated.Disclosure of relevant financial relationships are as follows:Dr. Bernstein discloses the following relevant financial relationships with ineligible companies:Advisory Board Consultant: Takeda/Shire, CSL Behring, KalVista, Pharming, Biocryst, Ionis, Intellia, Pharvaris, Astria and BiomarinGrant/Research Support: Takeda/Shire, CSL Behring, KalVista, Pharming, Biocryst, Ionis, Intellia, Pharvaris, Astria and BiomariSpeaker's Bureau: PharmingPlanners for this activity have no relevant financial relationships with any ineligible companies.This activity will review off-label or investigational information.The opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or CheckRare CE. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information.Accreditation and Credit DesignationIn support of improving patient care, this activity has been planned and implemented by American Academy of CME, Inc. and CheckRare CE. American Academy of CME, Inc. is Jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.PhysiciansAmerican Academy of CME, Inc., designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Other HCPsOther members of the care team will receive a certificate of participation.There are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre and post-program assessments. Your certificate will be emailed to you within 30 days.ContactFor any questions, please contact: CEServices@academycme.orgCopyright© 2025. This CME-certified activity is held as copyrighted © by American Academy of CME and CheckRare CE. Through this notice, the Academy and CheckRare CE grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s).

In the week since Donald Trump took office, he's caused quite the stir with healthcare-centered moves that include ordering the Department of Health and Human Services to stop communications, hiring and travel and announcing that he would withdraw the U.S. from the World Health Organization. Wednesday, the U.S. Senate Finance Committee convenes to vote on the controversial nomination of Robert F. Kennedy, Jr. for health secretary—a vote that Jefferies analysts said they expect to be “close.” Biogen continues to grab headlines this month, as the latest chapter in the Sage saga saw the smaller biotech rejecting its neuro partner's unsolicited buyout offer. Meanwhile, Biogen laid off an undisclosed number of employees from its research unit, just as a higher dose of its Ionis-partnered spinal muscular atrophy therapy Spinraza was accepted for review by both the FDA and EMA. Elsewhere, the weight loss space continues to click on all cylinders, with Versant Ventures debuting its newest obesity biotech Helicore Biopharma on Tuesday with $65 million in series A funds, and two obesity-focused companies, Aardvark Therapeutics and Metsera, seeking entry to the public markets. These up-and-comers will have to compete against the likes of Eli Lilly and Novo Nordisk, the latter of which reported data last week showing that its next-gen obesity drug amycretin could elicit up to 22% weight-loss. And Veru announced that its enobosarm could significantly improve the quality of weight loss in seniors also taking Novo's Wegovy. Another busy therapeutic space is Duchenne muscular dystrophy, where analysts predict a lot of action in the next couple of years, with a number of data readouts and regulatory submissions. And finally, Annalee Armstrong caught up at JPM with Novavax CEO John Jacobs, who said the vaccine maker is at a pivot point.

Hour one of DJ & PK for January 24, 2025: Utah Hockey Club game recap Jeremy Werner, 24/7 Sports Reno Mahe, Former BYU Cougar and Philadelpia Eagle

Hour two of DJ & PK for January 23, 2025: What is Trending Justin Werner, Illini Inquirer Will the Utah Jazz find a Shai Gilgeous-Alexander?

Justin Werner from Illini Inquirer joined DJ & PK to talk about Kasparas Jakučionis and what he would offer to a team like the Utah Jazz if they took him in the NBA Draft.

ENBO tinklalaidėje Mykolas Jankaitis, Rokas Grajauskas ir Paulius Viluckas naujausiame epizode aptaria svarbiausias NBA aktualijas. Diskusijoje analizuojamas skirtingas Kalėdų laikotarpio traktavimas abiejose lygose, Jimmy Butlerio karjeros kryptys bei „Kings“ trenerio atleidimo priežastys. Taip pat gilinamasi į „Lakers“ naujausius mainus ir jų poveikį komandai bei svarstoma, ar Jakučionis gali tapti vienu iš pirmųjų NBA naujokų biržos šaukimų. Visos svarbiausios temos vienoje vietoje! Tinklalaidės partneriai: – Nealkoholinis alus „Gubernija“, daugiau informacijos – https://gubernija.lt/ Temos: Skirtingas NBA ir Eurolygos dėmesys Kalėdoms (00:00); Butlerio vertė, nuopelnai ir naujos galimos kryptys (04:40); „Kings“ trenerio atleidimo priežastys ir tolimesnė klubo perspektyva (38:15);  Ar „Lakers“ mainai keičia klubo situaciją (1:02:58); Jakučionis – top 3 šaukimas? (1:16:20).

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.Novo Nordisk's weight loss drug, cagrisema, failed to meet investor expectations of achieving 25% weight loss, causing the stock to plummet. Galectin's stock also tumbled after its lead asset missed the primary endpoint in a phase IIb/III trial. On a positive note, Ionis' Tryngolza became the first FDA-approved therapy for familial chylomicronemia syndrome. GSK posted mixed survival data for the Jemperli/Zejula combo in first-line ovarian cancer treatment. Intelligencia AI accurately predicted high-potential biotechs before the ASH conference, showcasing the reliability of its AI-driven methodology. Overall, the biopharma industry is seeing a mix of successes and setbacks in various drug developments and approvals.

On this episode of Biotalk, Geoff Meyerson, CEO and Co-founder of Locust Walk, speaks with Sudhir Agrawal, Founder and President of ARNAY Sciences and a pioneer in RNA therapeutics. Sudhir's extensive career spans over three decades, during which he has made groundbreaking contributions to the field, including developing gapmer antisense technology, immune modulation approaches, and, in recent years, designing cyclic structures of DNA and RNA for therapeutic applications. In their conversation, Sudhir recounts his journey from his early days in nucleic acid research to becoming a leading innovator in RNA therapeutics. He delves into the origins of the gapmer technology, its impact on antisense drug development, and the lessons learned from his time Idera Pharmaceuticals. He also shares insights into his latest work on cyclic RNA/DNA structures and discusses his vision for the future of nucleic acid therapeutics. He concludes by offering practical advice to entrepreneurs aspiring to break into the biotech space and sharing his thoughts on the future of RNA science. Join us for a deep dive into the world of RNA therapeutics with one of its most influential figures.Subscribe or follow Biotalk on Apple Podcasts | Spotify. Timestamps: 1:34 What inspired you to focus specifically on RNA therapeutics, and how did your whole journey here begin?  3:04 Can you provide more details about the initial insight behind the development of the gapmer technology, which has been transformational for the space?  5:34 What lessons did you learn from your experience at Ionis (formerly Isis) that you would apply to your current work?  13:54 How are you thinking about commercializing the cyclic RNA/DNA structures you have developed at your company RNA Sciences?  23:40 Beyond the cyclic structures, what other innovations or areas of focus do you see on the horizon for nucleic acid therapeutics?  23:23 What advice would you give your early self starting out as an entrepreneur and innovator in the biotech space? 

Host James Oxford (@AotGScouting) is joined by Chris Filer (@UCLA_Chris) and Finn Vandergriff (@FinnDraft) to discuss early season play from Khaman Maluach, Dylan Harper, Kasparas Jakucionis, and Egor Demin.

Tuesday, October 22, 2024 First Principles Genetic disease means that gene broken since conception. Novel medicines are possible ways to fix the gene - Genetic Therapies (ASO &/or AAV), this is recent, before now, kids with these diseases were a “go home and love them” situation. These are delivered via spinal tap or directly to the brain in leading medical centers. First though, regulators must approve.   Our job Develop medicines or get industry to - This is happening see Pipeline Get regulators to approve trials Get medical centers up to speed on SYNGAP1-Related Disorders (SRD) What we are building on CHOP ENDD funded externally (see #S10e92) and replicating what was built for STXBP1, check last week's webinar https://curesyngap1.org/resources/webinars/93-endd-chop-2024-syngap1/ Rare-X platform for PRO collection Regulatory pathway being made clearer every day by Stoke (Dravet), Praxis (SCN2A), Ionis (many) all of whom are working on SYNGAP1 as well.   What we are asking for We need to raise at least $500k (3rd site), preferably $1.13M (ProMMiS) Make your largest gift ever to SRF Fundraise with friends and family ACES is now ProMMiS, who knew ACE meant Adverse Childhood Event, not us. Key slides: S1 Path to Treatment | 2024 (09.27.24) 1. Why Now?  Why is it time to go from bench to bedside (research to clinical)? At least 10 companies on our pipeline not to mention multiple small molecule efforts We have limited resources – so the focus has to transition, clinical funding first. CHOP Gift is 1 year down… 2. Why NHS?Understand SYNGAP1 better, go beyond Vlaskamp 2019 and Wiltrout 2024, see #S10e105  FYI at CHOP, as I shared in #S10e151, at year 1, we are at  – 86 (Visits) + 10 (new scheduled) + 19 (2nd) + 4 (3rd)  + 22 (follow up)  Learn what to measure in clinical trials for SRD, remember our seizures are challenging Ideally we develop a Synthetic Control Arm if we use GCP Why top shelf?  We need institutions the FDA will take seriously and our children are very complex requiring experienced clinicians.  3. Why Multidisciplinary. Neuro, Psych, Genetics, PT, ST, OT, GI, Sleep, ENT, Ortho. Beyond the sheer burden of getting our kids out and about for multiple appointments the coordination by a parent is almost impossible.   4. Why Multisite/3 sites?Replicable/scalable required by regulators Accessibility (not primary reason) Establish more locations where trials will be managed Laying a foundation for a national self-sustaining network 3 is the minimum, look at STARR or Angelman, both had/ve 4. 5. How and why so fast? Because we can.  Time is Brain. Following a well trodden path SMA, Rett, Angelman, Dravet, but we are moving FASTER. 6. Does the industry really care? We are next there are so so many behind us, eager to take the resources we have access to today. Market size (Per our Census 425 US/1500 global is tip of iceberg) Multiple players reassuring each other Relatively strong amount of scientific and clinical research Haploinsufficiency (like Dravet – STOKE) – so relatively easy 7. Expensive? No. Clinical Research is more expensive than basic scientific research. Leveraging CHOP and Rare-X, setting up required networks to prepare for clinical trials.  It's time. 8. Why Bother/Help? Now is the time for SYNGAP1, we miss it at our peril. Sure, once in these places we will still see our patients, but the study, the support and the focus may pass. Our kids don't die, regardless of patient age, what we are doing can change their future and that of their loved ones and caregivers. If not us, then who? It is a rare exception when a non-family member gives a gift, and it is always because a family member asked.  We must ask. 9. What can I do? Donate to, share, join our Coast2Coast Clinics Challenge – two SYNGAP1 Squads in West and East – it's critical $500k goal by end of 2024; more than $1M needed just for the SYNGAP1ProMMiS. So far, donations from $25 to $25,000 – each and every contribution matters. This requires our entire S1 network to solicit family, friends, work colleagues, companies, etc. to contribute. Many causes out there – why not ours? Syngap.Fund/C2C   https://Syngap.Fund/C2C > https://secure.givelively.org/donate/syngap-research-fund-incorporated/coast2coast-clinics-challenge   Two teams:  https://Syngap.Fund/West & https://Syngap.Fund/East

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.Florida has awarded additional Medicaid contracts to CVS, UnitedHealth, and Molina, after they were excluded from the first round of contracts in April. Meanwhile, Steward Health failed to attract qualified bidders during the first round of hospital sales. In other news, CMS has tightened rules for ACA brokers to prevent unauthorized plan switching. Commure is set to acquire AI scribe Augmedix in a $139 million deal to expand its documentation products. The healthcare industry is increasingly using AI to transform unstructured data and improve patient care. Additionally, online tools are being utilized to address gaps in mental healthcare services. AI and machine learning are also playing a crucial role in improving clinical trials by retaining participants, enhancing key performance indicators, and boosting query quality.The text discusses various updates in the medical technology industry on July 22, 2024. The FDA sent warning letters to Chinese syringe manufacturers, Embecta, a diabetes device firm, is considering a sale, Truvian raised $74 million for a blood test instrument, and a CrowdStrike outage affected US hospitals. Medtronic executive Stacey Churchwell spoke about the use of artificial intelligence in reducing false positives in cardiac monitors. Intuitive's Da Vinci 5 robot launch exceeded Wall Street expectations. The text also includes information on real-time vital signs data, Biden's healthcare legacy, and suggestions for further reading.Private biotech M&A activity has increased significantly, with acquisitions of private biotechs outpacing public offerings. Ionis is moving forward with plans for an Angelman drug that Biogen passed on, with a late-stage study set to begin next year. Meanwhile, J&J is seeking expanded approval for its antidepressant Spravato. The advanced therapeutic medicinal product (ATMP) sector is at the forefront of personalized medicine, with over 1,000 trials in development and potential disruption through manufacturing automation. In the oncology research space, there is fierce competition in the GLP-1 drug race as companies vie for a share of the obesity treatment market expected to surpass $100 billion by the end of the decade.Innovent's Phase III trial for their diabetes drug in China has been successful, bringing them closer to potential approval in the country. The drug, Mazdutide, is also being developed for weight management. Meanwhile, Lilly has received approval in China for their drug Tirzepatide for obesity, following Novo's approval for Semaglutide. Samsung Bioepis has received FDA approval for a biosimilar to AstraZeneca's Soliris. Novo and Lilly are looking to expand their GLP-1 pipelines beyond treating diabetes and obesity. Other news in the biopharma industry includes startups competing in the obesity space, GSK plotting Blenrep's return to market, and a procurement deal between IGA and the US government.Researchers in China conducted a small study using an "off the shelf" CAR-T cell therapy to treat patients with autoimmune diseases. The therapy, made with engineered cells from a healthy donor, resulted in deep remission of immune diseases and a reversal of inflammation and fibrosis in three patients after six months. This study marks a potential breakthrough in allogeneic CAR-T cell therapy for autoimmune diseases, offering a potentially cheaper and easier-to-manufacture alternative to approved autologous therapies. However, despite this progress, payment barriers need to be addressed to make these therapies accessible to patients. The study highlights the need for outside support to overcome barriers in the development and commercialization of cell and gene therapies. Additionally, the research landscape for cancer treatments continues to grow, with oncology being a significant area of growth for pharma drug development. The stud

In this podcast, Robert MacNeill, Professor Michael Bartlett of the University of Georgia and Dr. Guilherme Guimaraes of Biogen, will focus on oligonucleotide LC-MS covering the exciting key challenges, the pivotal nature of sensitivity in such assays, and the various analytical approaches and technologies that have been used, currently in use or being developed. The episode explores the following:How recent liquid chromatographic and mass spectral innovations have impacted the bioanalysis of these drug modalitiesWhere innovation is taking us particularly in terms of the increasing profile of high-resolution mass spectrometry and the push toward chromatographic miniaturizationSpeakers:Michael G. Bartlett, Ph.D., FAAPS – University Professor, Associate Dean for Science Education, Research and Technology, College of Pharmacy, University of Georgia  – Professor, Department of Metabolism, Digestion and Reproduction at Imperial CollegeOver the past 29 years at the University of Georgia, Dr. Bartlett's group has been involved in the development, validation and implementation of novel bioanalytical methodologies to advance biomedical research.  His laboratory works broadly in the areas of drug discovery, development and toxicology resulting in over 190 peer-reviewed publications in a wide variety of areas.  His research has been supported by the NIH, EPA, DOD, ACS and industry.   One area where Dr. Bartlett's lab has gained particular notoriety is in the use of LC-MS to analyze oligonucleotides. This work began during his time at the University of Utah but has accelerated over the past 15 years. Dr. Bartlett's group has studied many aspects involved in the use of LC-MS to evaluate therapeutic oligonucleotides for quality control, bioanalysis, pharmacokinetics and metabolism. They have also adapted many of these approaches to analyze microRNAs as potential disease biomarkers.  Finally, they have actively worked with many companies on the use of LC-MS to determine oligonucleotides including Pfizer, Ionis, ProQR, Newomics and Waters.   Guilherme Guimaraes – Scientist DMPK at Biogen Dr. Guilherme (Gui) Guimaraes is a scientist in drug metabolism and pharmacokinetics at Biogen. He is responsible for bioanalytical analysis of small molecules and antisense oligonucleotides.  Gui holds a Ph.D in pharmaceutical and biomedical sciences and a masters in international biomedical regulatory sciences from the University of Georgia. His graduate work was focused on the application of novel analytical strategies to improve the chromatographic performance and sensitivity of oligonucleotide LC-MS methods. Some of these strategies include the use of low adsorption surfaces and HILIC microflow LC – nanoelectrospray MS.  Stay tuned for more podcasts in our Pharmaron DMPK Insights Series!

After deciphering the first part of the prophecy revealed by Sara Benthem, the adventurers journey to Briarcleft Forest with the assistance of R&R Brigade ally Ionis. Following a lead given to them by Professor Roundland, they seek out the Gem of Fire. Featuring special guest Sam Richardson! Learn more about your ad choices. Visit megaphone.fm/adchoices

00:00:00 Surf's Up, Season 5 Episode 20Naim Alkhouri and Mazen Noureddin join co-hosts Jörn Schattenberg and Roger Green to discuss major drug development stories from the EASL Congress 2024. They pay tribute to Stephen Harrison and proceed to groundbreakers.00:08:16 - Presentations on ResmetiromMazen shares a paper he presented looking at resmetirom dose-response. The 100mg dose performed better than the 80mg dose. Jörn notes that the most important element of the study might be the demonstrated 36-month effect.  00:14:19- Implications of Different Analytical Modes Naim compares different modes of analysis. Intent to Treat, which treats all non-completers as failures, will produce lower rates of response than a "completer" or "modified Intent to Treat" analysis, which either eliminates non-completers or assigns them placebo-level response. 00:16:12 - The "Twin-Cretins"Jörn coined  the name "Twin-cretins" for agents with GLP-1 agonism plus another incretin effect. Tirzepatide is a GLP/GIP while survodutide, pemvuditide, and efinopegdutide, are GLP/glucagons. Naim reviews the tirzepatide late-breaker presentation, which showed high rates of MASH resolution, but, as a completer analysis, might not have proven whether a GLP/GIP can achieve significant fibrosis regression.  Naim notes that Stephen doubted strongly this was possible, but that bariatric surgery's effect creates a paradox. Mazen concurs, and states he is more confident in the GLP/glucagon agents. Jörn agrees. 00:23:09 - Implications of widespread GLP useRoger asks how widespread prior patient use of incretins will affect prescribing. Naim states that many of his Rezdiffra MASH patients have been on GLP-1 already.  He describes a key difference between the three GLP/glucagon agents in development. 00:24:20 - The previous GLP/glucagon studiesNaim expresses his excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed a further reduction in liver fat compared to the GLP-1 agent. 00:26:44 - Safety of survodutide in cirrhosisJörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He reviews survodutide data from the NEJM article.  00:29:41 - FGF-21s, starting with efrux data Focus shifts to FGF-21s. Mazen shares data from the efruxifermin late-breaker, a 96-week, triple biopsy study showing dramatic, sustained one- and two-level fibrosis improvement. Jörn notes the design demonstrates durability, which Roger finds particularly encouraging given the pegbelfermin experience. Naim  adds that a sustainable two-stage drop in fibrosis might position FGF-21 as induction therapy before long-term oral maintenance.   00:35:28 - Is a drug-based MASH "cure" possible? Mazen wonders whether sustained FGF-21 efficacy might return livers to their "normal" state, almost like a "cure." Jörn briefly discusses pegozafermin, and Mazen notes that a third FGF-21 is in development.   00:42:22 - Wrap-up The panel covers three other agents: the FASN inhibitor, denifenstat, Ionis's DGAT-2 antisense inhibitor, ION224, and Takeda's TAK-227, a TG2 inhibitor, plus the results of SPECIAL, a study evaluating the effect of bariatric surgery on people with cirrhosis. After these, Roger asks Mazen and Jörn what they consider likely to be the biggest story at AASLD in November.  00:53:03 - Question of the Week Given this discussion, Roger asks what are likely to be the three most prescribed medications for MASH five years from now.  00:53:36 - Business Report The next EASL Congress review episodes, how to attend recording sessions live, and a vault discussion from last year's EASL Congress wrap-up. 

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

JOIN SRF LT on Thursday: Volunteer Info session with Leadership Team is this week:  https://syngap.fund/LT Thursday 5/23 at 5:30 Pacific.   MDBR is 3 weeks away! https://Syngap.Fund/Unite   $5k match https://x.com/phalliburton/status/1792288377049415835   It's all about therapies.  Precision Genetic and Repurposed.   Conferences are where we engage professional communities around SYNGAP1 & SRF.  - Last week I was at Milken Global.  All diseases are talking about biomarkers & endpoints. https://milkeninstitute.org/events/global-conference-2024/program  - This week I was at the #Ultragenyx Bootcamp with our CSO https://www.ultragenyx.com/video-this-bootcamp-helps-parents-advance-rare-disease-research/ So good to see Kathryn energized by this role.  - ASGCT was last week and that means announcements…  - Kathryn and I are off to BIO in June in San Diego.   Ionis for Angelman https://www.linkedin.com/posts/cureangelman_exciting-news-for-the-angelman-syndrome-community-activity-7196872264976322563-_rvX  Capsida for STX https://www.linkedin.com/posts/graglia_capsida-biotherapeutics-presents-new-preclinical-activity-7194004214635716608-M01Y  Encoded for STX https://www.linkedin.com/posts/stxbp1-foundation_encoded-therapeutics-provides-pipeline-updates-activity-7196942568859787265-leKO  Nasha at FOXG1 https://www.youtube.com/watch?v=ELKijSx0uwQ   Repurposed therapies are just as important.   Cost effective.  Globally available. They are here now.  We must act, the suffering is immense. They show us what is improvable and therefore inform clinical trial design. They are not compromising other trials.  And to even suggest that is unethical if it suggests people should hold off on helping patients.  How about we just diagnose more kids?  Or think harder about which kids go to which trials? Precision Genetic Therapies are going to be more effective than repurposed drugs, people will happily participate in trials.   Review of repurposed drugs: RAVICTI Rx- 10+ patients with Dr. Grinspan, not all but a few have had significant seizure reduction.  I remain worried about cost and look to STXBP1 and SLC6A1 for guidance here. NORTRIPTYLINE Rx - Has helped me, a handful of families are getting a Rx.  I am hopeful that some researcher does an investigator led trial.  But until then, ask your Neuro. ACETYL-LEUCINE is a Nutraceutical - Update 1 has really been noticed and Update 2 will share a few potential mechanisms of action.  Many are trying this drug from https://bit.ly/tanganil24 Encouraging… no, updating.  Please share data with us if you are trying.  We are collecting case studies for Update 3.  Thank you to the team here.   NEWLY DIAGNOSED? New families have resources here! https://syngap.fund/Resources SOCIAL MATTERS - AMPLIFY SRF TO MAKE SURE FAMILIES FIND US  - 1,010 YouTube.  https://www.youtube.com/@CureSYNGAP1   - 9,900 Twitter https://twitter.com/cureSYNGAP1  - 3,560 LinkedIn.  https://www.linkedin.com/company/curesyngap1/ - 49k TikTok https://www.instagram.com/curesyngap1/ Podcasts, give all of these a five star review! SRF Channel - https://podcasts.apple.com/us/channel/syngap1-podcasts-by-srf/id6464522917 Episode 141 of #Syngap10 - May 20, 2024 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat #F78A1 #CureSYNGAP1

This week on “The Top Line,” we're joined by Fierce Biotech Senior Editor Annalee Armstrong and Fierce Pharma Marketing Senior Editor Ben Adams. We're diving into our recent spin on March Madness at Fierce. This time around, Fierce Biotech kicked off its inaugural Best Biotech Name tournament, while over at Fierce Pharma Marketing, we held our biannual Drug Names tournament. The editors discuss what makes a company or drug name tick, what to steer clear of, and how the entire competition played out.  To learn more about the topics in this episode:  #FierceMadness: AstraZeneca and Ionis cruise to victory as Wainua trounces Lilly's Mounjaro for the tournament win #FierceMadness: The Best Biotech Name Tournament—A champion is CROWNED See omnystudio.com/listener for privacy information.

Conference season is in full swing, with the American Association for Cancer Research and American College of Cardiology concurrently holding their annual meetings in San Diego and Atlanta, respectively. From opposite coasts, biopharma companies are presenting their latest data in the cancer and cardiology spaces, both hits and misses alike. Oncology continues to be a hot area for investment, with several highly anticipated readouts coming down the pike. In addition to all the data coming out of AACR, conference organizers this year put together the meeting's first-ever industry event, bringing together investigators, investors and Big Pharma. Over at ACC, one exciting race to watch will be between Ionis and Arrowhead, both of whom presented positive data on their ApoC3-targeting drugs for diseases associated with elevated triglyceride levels. Meanwhile, as the BIOSECURE Act sits before Congress, biopharma companies detail the potential fallout to the growing geopolitical tensions between the U.S. and China.

On this week's episode of Biotech Hangout, hosts Daphne Zohar, Brad Loncar, Tim Opler, Michal Preminger, Eric Schmidt and Yaron Werber discuss the latest biotech news, including commentary on the biotech sector performance in 2024 and a pharma R&D investment overview. The hosts cover the week's notable M&A, including AstraZeneca's acquisition of Amolyt plus Novartis' acquisition of IFM Due and a related discussion on option-to-buy deals. The group also discusses Ionis meeting the primary endpoint in its Phase 2 MASH trial and Madrigal's historic accelerated approval for NASH/MASH. Other topics include Eli Lilly's partnership with Amazon pharmacy to dispense prescription medicines and the impact of cutting out the middle man, as well as anticipated regulatory updates for Legend and 2Seventy Bio. The hosts weigh-in on the BioSecure Act that led BIO to cut ties with WuXi and the impact the bill may have on other Chinese CROs. The group also flagged recently reported Phase 2 data for Silence Therapeutics' Lp(a) therapy and Acadia's schizophrenia treatment pimavanserin fails Phase 3 study. *This episode aired on March 15, 2024.

On this week's Biotech Hangout, hosts Daphne Zohar, Brad Loncar, Josh Schimmer, Eric Schmidt and Yaron Werber discuss the latest biotech news, including the IPO window creaking back open and aftermarket performance up 12-19% for secondary offerings and IPOs. The hosts also discuss the FTC challenges facing industry M&A and another roadblock for AbbVie's Cerevel deal. The retirement of AbbVie CEO Richard Gonzalez prompts a discussion amongst the hosts on important qualities of a CEO. A range of FDA-related news from the week is also covered including the approval of Iovance's Amtagvi as first T-cell therapy for a solid tumor; Ionis and AstraZeneca's fast track designation for Phase 3 ATTR-CM drug eplontersen; two drug trials at Rapt Therapeutics put on hold; the review of Sarepta's Elevidys for traditional approval; United Therapeutic's litigation and Alnylam's endpoint changes to Phase 3 study design for Amvuttra. Other topics include Bayer slashing its dividend by 95%, IQVIA's global R&D trends report, and a discussion on the biotech business model sparked by news that Regeneron and Vertex have crossed the $100B market cap threshold. *This episode aired on February 23, 2024.

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.The FDA has posted guidance on cybersecurity for medical device companies seeking authorization for new devices. Mass General Brigham is collaborating with the FDA to create a brain-computer interface group to address challenges facing developers of such devices. Moody's predicts that AI will expand medtech portfolios and revenue streams in the next two years. Abbott has recalled its HeartMate LVAD communication system due to reported injuries linked to the device malfunctioning. 3M has named William Brown as CEO, replacing Michael Roman. The medical device industry is seeing a trend towards incorporating AI and digital health technologies.The FDA has raised safety concerns about early patient deaths in those treated with Bristol Myers Squibb's Abecma and Johnson & Johnson's Carvykti ahead of an advisory committee meeting. In other news, the Alabama Supreme Court's ruling on in vitro fertilization has caused political blowback and uncertainty in the market. Additionally, Lilly has made its weight-loss drug Zepbound available through Amazon Pharmacy, and Ionis' antisense molecule has shown positive results in a Phase II trial for liver disease. Novartis has acquired IFM Due in a deal potentially worth $835 million, and the FDA is questioning the benefit-risk profile of Geron's MDS candidate.Heinz is launching a campaign to promote gravy as more than just a holiday condiment, leveraging its iconic status to encourage consumers to use gravy like they use ketchup. "Godzilla x Kong" has released Roblox's first immersive movie trailer, allowing players to be swept into a virtual game after watching a 2D teaser. Meta announced updates to Advantage+ and shopping ads, while Barkley and OKRP have merged to create a "big indie" agency. Marketing Dive provides insights into news and trends shaping the marketing and advertising industry, covering topics such as marketing technology, social media, video marketing, analytics, and more.

ESC TV Today brings you concise analysis from the world's leading experts, so you can stay on top of what's happening in your field quickly. This episode covers: Cardiology This Week: A concise summary of recent studies Management of cardiac amyloidosis e-cigarettes and cardiovascular disease Statistics Made Easy: The Hazard Ratio Host: Susanna Price Guests: Carlos Aguiar, Julian Gillmore, Maryam Kavousi Want to watch that episode? Go to: https://esc365.escardio.org/event/1144   Disclaimer  This programme is intended for health care professionals only and is to be used for educational purposes. The European Society of Cardiology (ESC) does not aim to promote medicinal products nor devices. Any views or opinions expressed are the presenters' own and do not reflect the views of the ESC.   Declarations of interests Stephan Achenbach, Maryam Kavousi, Nicolle Kraenkel and Susanna Price have declared to have no potential conflicts of interest to report. Carlos Aguiar has declared to have potential conflicts of interest to report: personal fees for consultancy and/or speaker fees from Abbott, AbbVie, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Ferrer, Gilead, Lilly, Novartis, Pfizer, Sanofi, Servier, Tecnimede. Davide Capodanno has declared to have potential conflicts of interest to report: Sanofi, Novo Nordisk, Terumo, Medtronic. Julian Gillmore has declared to have potential conflicts of interest to report: consultancy for Alnylam, ATTRalus, AstraZeneca, Bridgebio, Intellia, Ionis, Lycia. Emma Svennberg has declared to have potential conflicts of interest to report: institutional research grants from Abbott, Astra Zeneca, Bayer, Bristol-Myers, Squibb-Pfizer, Boehringer-Ingelheim, Johnson & Johnson, Merck Sharp & Dohme.

In the first Biotech Hangout of 2024, RA Capital's Peter Kolchinsky joins hosts Daphne Zohar, Josh Schimmer, Tim Opler, Paul Matteis and Luba Greenwood to discuss the latest biotech news. They start with the last M&A deals of 2023 including Bristol Myers Squibb's acquisition of Karuna and Rayzebio, and AstraZeneca's acquisition of Gracell. They discuss insights from RA Capital's latest sector analysis and the outlook for the sector in 2024, plus JPM predictions. The hosts also cover news from the first week of 2024 including Longboard Pharmaceuticals and Dyne Therapeutics data, Novartis' expanded collaboration with Voyager, the FDA's hold on Iovance's TIL therapy and their approval of AstraZeneca and Ionis' rare nerve disease treatment. Other topics include Goldman Sachs life science investment fund and ImmunityBio's royalty financing. *This episode aired on January 5, 2024

Tapk KALBA MAMOS bendruomenės dalimi ir klausyk pilnų pokalbių, dalyvauk mamų rytmečiuose, Discord'o pokalbiuose, Knygų klube bei kitose tik bendruomenei skirtose veiklose. Visą informaciją rasi ⁠⁠⁠⁠⁠www.kalbamamos.lt⁠⁠⁠. Nori tik klausytis pokalbių? Prenumeruok tinklalaidę KALBA MAMOS „Spotify“ platformoje. Pokalbiui apie tikslus ir įpročius pakviečiau gydytoją psichoterapeutą Dainių Jakučionį, kuris jau daugiau nei 15 metų gilinasi į su žmogaus kūnu ir protu susijusius klausimus, o pastaruosius 10 metų aktyviai konsultuoja kaip psichoterapeutas. Jis veda mokymus ir skaito pranešimus įvairiose konferencijose, susijusiose su psichologine gerove ir psichine sveikata, o taip taip pat yra programėlės „Sensa“, padedančios susidoroti su psichologiniais sunkumais, bendraautorius. Dainius Jakučionis socialiniuose tinkluose dalinasi psichologinėmis įžvalgomis, skirtomis asmeninei saviugdai. Man atrodo, kad sausio tema apie tikslus ir įpročius yra tam tikras mūsų gruodžio temos tęsinys, kai kvietėme stabtelėti ir peržvelgti prabėgusius metus, paklausti savęs, kas mums patiko, praturtino, kokias pamokas išsinešame į kitus metus, ką norėtume tęsti, o ko – ne. Dabar man norisi kviesti pokalbiui ne apie tai, kaip nuversti kalnus, bet kaip iš tiesų išgirsti, suprasti, ko aš noriu, dėl ko dega mano širdis ir kokius žingsnius, nors ir labai mažus, galiu kasdien žengti to tikslo ar tikslų link? Šiame pokalbyje kalbėsime apie: kodėl ši, tikslų, tema mus galbūt erzina, o gal net ir žmonės, kurie kelia sau kažkokius tikslus ir viešai apie tai dalinasi? Ar verta susirūpinti, jei neturime šiuo metu jokių tikslų? Kodėl svarbu atskirti norus, svajones nuo tikslų ir pasidžiaugti kiekvienu žingsniu, kurį žengiame tikslo link. Apie baimes. Kodėl bijome kelti tikslus ir iš kur tos baimės atsiranda? Apie nusivylimus. Kodėl neverta nusivilti, bet verta bandyti vėl ir vėl iš naujo. Apie perfekcionizmą. Kodėl daug vertingiau pastovumas darant nors ir labai mažus žingsnelius, bet daryti, o ne sustoti, nes neišeina pasiekti tobulo rezultato. Pokalbiui baigiantis dar turėjau pilną kišenę klausimų, bet laiko yra tiek, kiek yra, sąlygos tokios, kokios yra, ir paleidžiu šį pokalbį su viltimi, kad bet kokiu atveju išsinešite iš jo gerų, įkvepiančių, padrąsinančių minčių. Gero klausymo! Marija

Good morning from Pharma and Biotech Daily, the podcast that gives you only what's important to hear in the Pharma and Biotech world. Today, we have some exciting news in the industry. Johnson & Johnson (J&J) is set to acquire ADC drug developer Ambrx for $2 billion, joining other pharma companies in the antibody-drug conjugate (ADC) space. This acquisition shows the growing interest in ADCs and their potential to revolutionize cancer treatment. In other news, Merck is making a move in the cancer biotech sector by acquiring struggling company Harpoon for $680 million. This strategic move will strengthen Merck's portfolio and expand its presence in the oncology field. Shifting gears, gene editing startup Metagenomi has filed for an IPO. With several preclinical programs in development with Moderna, Ionis, and Affini-t, Metagenomi is poised for success in the gene editing market. Looking ahead, there are five FDA decisions to watch in the first quarter of 2024. This includes new drug verdicts from Eli Lilly and Merck, as well as the potential approval of the first tumor-infiltrating lymphocyte (TIL) therapy. These decisions have the potential to shape the future of medicine and provide new treatment options for patients. Now let's talk about some of the challenges facing emerging biotech companies in 2024. One challenge is an unusual Federal Trade Commission (FTC) challenge that could have implications for the entire sector. Additionally, there is a question of whether the sector's recent momentum will end a funding crunch. It will be interesting to see how these challenges are addressed and how they impact the industry as a whole. Lastly, let's not forget about the advancements in cell therapy research. The approvals of cell- and gene-based medicines in recent years have given young drugmakers a path to pursue in the field of cell therapy research. This exciting area of research has the potential to revolutionize medicine and provide new treatment options for patients. In conclusion, the Pharma and Biotech industry is buzzing with activity. From major acquisitions to promising startups and upcoming FDA decisions, there is a lot to keep an eye on. Additionally, the use of generative AI in biopharma companies is improving processes and boosting productivity. We can expect even more exciting developments in the future. That's all for today's episode of Pharma and Biotech Daily. Stay tuned for more updates and news in the industry. Thank you for listening!

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in the Pharma and Biotech world. Today, we have a lot of news to cover, so let's dive right in.## Agilent, a global healthcare company, plans to lay off around 400 workers, which represents about 2% of its global workforce. Most of the layoffs will be completed in the first quarter of next year. In other news, Philips has issued a recall of its MRI machines due to the risk of explosion. The Food and Drug Administration has labeled the recall as a class I event, and there has been one reported incident of a machine exploding in the 22 years the system has been in use. Moving on, ResMed, another medical technology company, has warned about the risk of mask magnets interfering with medical implants. Like Philips, ResMed advises patients not to wear magnetized masks near certain implants. Cybersecurity incidents and vulnerabilities have affected the medtech sector in 2023. From vulnerable medical devices to system breaches, cybersecurity has been a major concern for the industry this year. In merger and acquisitions news, Illumina, a DNA sequencing leader, has finally agreed to unwind its $8 billion acquisition of cancer screening developer Grail. This decision comes after pressure to undo the acquisition since its inception. Several top medtech companies have announced layoffs this year as they implement cost-cutting measures. Johnson & Johnson, Medtronic, and Abbott are among the companies that have made staff reductions. Overall, 2023 has seen a slump in medtech mergers and acquisitions (M&A), but analysts predict an uptick in M&A activity in 2024.Lastly, there have been several medtech spinoffs that have reshaped the industry this year, with GE Healthcare, Johnson & Johnson, and Danaher completing transactions. Baxter, 3M, and Medtronic are expected to make their moves next.## In other news, Sarepta is seeking FDA approval to expand the use of its gene therapy treatment, Elevidys, for patients with Duchenne muscular dystrophy. This comes after a confirmatory trial for the treatment failed to meet its main goal. Bristol Myers is set to acquire brain drug developer Karuna for $14 billion, giving the company access to an experimental treatment for schizophrenia. The treatment is expected to become a blockbuster product. Ionis and AstraZeneca have received FDA approval for their drug Wainua, which competes with Alnylam's drug for the treatment of transthyretin amyloidosis. The approval opens up a new front in the long-running commercial battle between Ionis and Alnylam. Biotech M&A activity is picking back up, with Bristol Myers and AbbVie both making multibillion-dollar acquisitions in the neuroscience space. As ALS research continues to grow, the Healey Center has become a leading center for research and care for patients with ALS. However, the complexities of the disease and drug development have presented challenges and setbacks.## Shifting gears, the text discusses various healthcare-related topics. It mentions that antitrust enforcements in the healthcare industry reached a high in 2022, with health deals being impacted. It also highlights a class-action lawsuit filed against an Ohio hospital and its vendor after a data breach that potentially exposed the data of nearly nine million people. The text includes an opinion piece that predicts trends in healthcare mergers and acquisitions for 2024, such as a shift in funding sources and new regulatory policies. Additionally, it mentions a study that found clinician accuracy suffers from biased artificial intelligence, even with mitigation efforts. The text also briefly mentions the challenges facing interoperability in U.S. healthcare due to legislation, varying data standards, and privacy concerns. Moving on, Sanofi has abandoned the development of an antibody-drug conjugate (ADC) after a setback in a study. The ADC, acquired through a deal with Immu

Kas yra meilė? Klausimas į kuri atsakyti atrodytų beveik neįmanoma, tačiau kiekvienas tvirtai tikime, kad žinome, kas ji yra. Nors gyvybės mokslų atstovai meilę pavadintų tiesiog cheminių procesų nulemtą prieraišumą individui, kuomet mūsų smegenyse išsiskiria meilės hormonas oksitocinas, visgi ją kiekvienas suprantame skirtingai, o taip pat turime įsitikinimus, kas ką gali ir ko negali mylėti.Sociologas Linas Jakučionis gilinosi ne tik į tai kaip nepriklausomos Lietuvos pradžioje užaugę vilniečiai aiškina meilės reiškinį, bet ir bandė suprasti, ką lietuviai galvoja apie romantinius santykius su humanoidiniais robotais.Pokalbis su sociologu Linu Jakučioniu apie besikeičiančią meilės sampratą, jos (i)racionalumą ir jausmus robotams.Ved. Ignas Klėjus

For more information regarding this CME/CE activity and to complete the CME/CE requirements and claim credit for this activity, visit:https://www.mycme.com/courses/using-glp-1-ras-to-reduce-cv-risk-in-t2d-9134SummaryType 2 diabetes (T2D) doubles a patient's risk for atherosclerotic cardiovascular disease (ASCVD), which is the leading cause of morbidity and mortality in patients with T2D. The 2023 ADA guidelines now recommend consideration of GLP-1 RAs in patients with T2D and ASCVD or indicators of ASCVD risk, independently of A1C and metformin use. In this episode, Dr. Pam Taub reviews recent updates in the cardiovascular benefits and appropriate use of GLP-1 receptor agonists for managing patients with T2D.Learning Objectives Incorporate early use of GLP-1 RA therapy in appropriate patients with T2D using a holistic approach, considering administration route and optimal dosingOvercome barriers to GLP-1 RA uptake and medication adherence in T2D through patient counseling to manage adverse effectsThis activity is accredited for CME/CE CreditAssociation of Black Cardiologists, Inc. (ABC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Association of Black Cardiologists, Inc. (ABC) designates this enduring material for a maximum of 0.25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.This activity has been planned and implemented in accordance with the Accreditation Standards of the American Association of Nurse Practitioners® (AANP) through the joint providership of the National Association for Continuing Education (NACE) and ABC. NACE is accredited by the AANP as an approved provider of nurse practitioner continuing education. Provider number 121222. This activity is approved for 0.25 contact hours (which includes 0.25 hours of pharmacology).For additional information about the accreditation of this program, contact NACE at info@naceonline.com.Summary of Individual DisclosuresDr. Taub financial relationships:Consultant: Amgen, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Esperion, Merck, Sanofi, Medtronic Contracted Research: Amgen, Novartis All her disclosures are related to cardiologyDr. Morris financial relationships: Consultant and advisor: Acorai, Regeneron, MerckSpeaker: Abbott, BI Lilly, Cytokinetics, Edwards Lifesciences, Ionis Contracted Research: Boston Scientific, Cytokinetics, Ionis, Merck, Myokardia, Novartis Stocks: Gilead Sciences All her disclosures are related to heart failure.All of the relevant financial relationships listed for these individuals have been mitigated.Association of Black Cardiologists Planning CommitteeTierra Dillenburg has no relevant conflicts of interest with any ACCME-defined commercial interest.Faculty, planners, guest patient(s) (if applicable), and moderators for this educational activity not listed in the Summary of Individual Disclosures above have no relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.Disclosure of Commercial Support This educational activity is supported by an independent educational grant from Novo Nordisk Inc.Please visit http://naceonline.com to engage in more live and on demand CME/CE content.

There was time during the early 70's when the field of oncology began to take hold where the singular focus was to extend the patient's life. In this ASCO Education podcast, our guest was one of the first to challenge that notion and rethink methods that focused the patient's QUALITY of life. Dr. Patricia Ganz joins us to describe her transition from cardiology to oncology (6:00), the moment she went beyond treating the disease and began thinking about treating the WHOLE patient (10:06) and the joy of the increasing numbers of patients who survive cancer (21:47).  Speaker Disclosures Dr. David Johnson: Consulting or Advisory Role – Merck, Pfizer, Aileron Therapeutics, Boston University Dr. Patrick Loehrer: Research Funding – Novartis, Lilly Foundation, Taiho Pharmaceutical Dr. Patricia Ganz: Leadership - Intrinsic LifeSciences  Stock and Other Ownership Interests - xenon pharma,  Intrinsic LifeSciences, Silarus Therapeutics, Disc Medicine, Teva,  Novartis, Merck. Johnson & Johnson, Pfizer, GlaxoSmithKline, Abbott Laboratories Consulting or Advisory Role - Global Blood Therapeutics, GSK, Ionis, akebia, Rockwell Medical Technologies, Disc Medicine, InformedDNA, Blue Note Therapeutics, Grail Patents, Royalties, Other Intellectual Property - related to iron metabolism and the anemia of chronic disease, Up-to-Date royalties for section editor on survivorship Resources If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT  Disclosures for this podcast are listed on the podcast page.   Pat Loehrer: Welcome to Oncology, Etc., an ASCO Education Podcast. I'm Pat Loehrer, Director of Global Oncology and Health Equity at Indiana University.  Dave Johnson: And I'm Dave Johnson, a Medical Oncologist at the University of Texas Southwestern in Dallas. If you're a regular listener to our podcast, welcome back. If you're new to Oncology, Etc., the purpose of the podcast is to introduce listeners to interesting and inspirational people and topics in and outside the world of oncology. Pat Loehrer: The field of oncology is relatively new. The first person treated with chemotherapy was in the 1940s. Medical oncology was just recognized as a specialty during the 1970s. And while cancer was considered by most people to be a death sentence, a steady growth of researchers sought to find cures. And they did for many cancers. But sometimes these treatments came at a cost. Our next guest challenged the notion that the singular focus of oncology is to extend the patient's duration of life. She asked whether an oncologist should also focus on addressing the patient's quality of life.  Dave Johnson: The doctor asking that question went to UCLA Medical School, initially planning to study cardiology. However, a chance encounter with a young, dynamic oncologist who had started a clinical cancer ward sparked her interest in the nascent field of oncology. She witnessed advances in cancer treatment that seemingly took it from that inevitable death sentence to a potentially curable disease. She also recognized early on that when it came to cancer, a doctor must take care of the whole patient and not just the disease.  From that point forward, our guest has had a storied career and an incredible impact on the world of cancer care. When initially offered a position at the West LA VA Medical Center, she saw it as an opportunity to advance the field of palliative care for patients with cancer. This proved to be one of her first opportunities to develop a program that incorporated a focus on quality of life into the management of cancer. Her work also focused on mental, dietary, physical, and emotional services to the long-term survivors of cancer.  That career path has led to many accomplishments and numerous accolades for our guest. She is a founding member of the National Coalition for Cancer Survivorship, served as the 2004 Co-chair of ASCO's Survivorship Task Force, and currently directs UCLA's Cancer Survivorship Center of Excellence, funded in part from a grant from Livestrong. Our guest is Dr. Patricia Ganz. Dr. Patricia Ganz: It's great to be with both of you today. Dave Johnson: We always like to ask our guests a little about their background, where they grew up, a little about their family. Dr. Patricia Ganz: Yes. I grew up in the city of Beverly Hills where my parents moved when I was about five years old because of the educational system. Unlike parts of the East Coast, we didn't have very many private schools in Los Angeles, and so public education was very good in California at that time. So I had a good launch and had a wonderful opportunity that many people didn't have at that time to grow up in a comfortable setting. Dave Johnson: Tell us about your mom. I understand she was a businesswoman, correct? Dr. Patricia Ganz: Yes, actually, my parents got married when my mom was 19 and my dad was 21. He was in medical school at the University of Michigan. His father and mother weren't too happy with him getting married before he could support a wife. But she worked in a family business in the wholesale produce business in Detroit. One of six children, she was very involved with her family in the business. And they were married, and then World War II started, my father was a physician in the military, so she worked in the family business during the war. After finally having children and growing up and being in Beverly Hills, she sat back and was a homemaker, but she was always a bit restless and was always looking for something to do. So wound up several years later, when I was in my early teens, starting a business with one of my uncles, an automobile parts business. They ultimately sold it out to a big company that bought it out.  Pat Loehrer: Where did your father serve in World War II? Dr. Patricia Ganz: He was actually D-Day Plus 21. He was in Wales during the war. They had to be stationed and moved down into the south before he was deployed. I have my parents' correspondence and letters from the war. He liberated some of the camps. Actually, as I have learned about the trauma of cancer and post-traumatic stress that happens in so many people, our military veterans, most recently, I think he had post-traumatic stress. He didn't talk very much about it, but I think liberating the camps, being overseas during that time, as it was for that silent generation, was very profound in terms of their activities.   He wound up practicing medicine, and Los Angeles had a practice in industrial medicine, and it was a comfortable life. He would work early in the morning till maybe three or four in the afternoon and then go to the gym, there were moonlighting physicians who worked in the practice. But I kind of saw an easy kind of medicine, and he was always very encouraging and wanted me to go into medicine -- that I could be an ophthalmologist or a radiologist, good job for a woman. But I didn't really see the tough life of some of the internists and other people who were really working more 24/7, taking care of patients in the way medicine used to be practiced. Dave Johnson: Yeah. So you were interested in, early in your career, in cardiology. Could you tell us about that, and then a little bit more about the transition to oncology?  Dr. Patricia Ganz: I went away to college, I went to Harvard Radcliffe and I came home during the summers. And was interested in doing something during the summer so I actually in a pediatric cardiology research laboratory as a volunteer at UCLA for a couple of summers between my freshman and sophomore year then my sophomore and junior year. And then I actually got a California Heart Association Fellowship between my junior and senior year in college.  And this pediatric cardiology lab was very interesting. They were starting to give ketamine, it had an identification number, it wasn't called ketamine. But they were giving it to children in the cardiac cath lab and then were very worried about whether it would interfere with measuring the pressures in the heart. So we had intact dogs that had catheters implanted in the heart, and the drug would be given to the animals and we would then measure their pressures in the heart.  That cardiology experience in 1970, the summer between my first and second year of medical school, the Swan-Ganz catheter was being tested. I worked at Cedars that summer and was watching them do the various studies to show the value of the catheter. And so by the time I was kind of finishing up medical school, I'd already invested all this time as an undergraduate. And then a little bit when I was in medical school and I kind of understood the physiology of the heart, very exciting. So that's kind of where I was headed until we started my internship. And I don't know if any of you remembered Marty Cline, but he was the oncologist who moved from UCSF to Los Angeles to start our hem-onc division. And very exciting, a wonderful bedside teacher.   And so all of a sudden, I've never been exposed to oncology and this was very interesting. But at the same time, I was rotating through the CCU, and in came two full-arrest patients, one of whom was a campus cop who was very obese, had arrested at his desk in the police station. And we didn't have emergency vehicles to help people get on campus at that time. This was 1973 or 1974, something like that. And he came in full arrest, vegetable. And then another man had been going out of his apartment to walk his dog and go downstairs, and then all of a sudden his wife saw him out on the street being resuscitated by people. And he came in also in full arrest.   So those two experiences, having to deal with those patients, not being able to kind of comfort the families, to do anything about it. As well as taking care of patients in my old clinic who had very bad vascular disease. One man, extremely depressed with claudication and angina, all of a sudden made me feel, “Well, you know what? I'm not sure I really want to be a cardiologist. I'm not sure I like the acute arrest that I had to deal with and the families. And also, the fact that people were depressed and you couldn't really talk to them about how serious their disease was.” Whereas I had patients with advanced cancer who came in, who had equally difficult prognoses, but because of the way people understood cancer, you could really talk about the problems that they would be facing and the end-of-life concerns that they would have.  So it was all of those things together that made me say, “Hmm.” And then also, Pat, you'll appreciate this, being from Indiana, we were giving phase II platinum to advanced testicular cancer patients, and it was miraculous. And so I thought, “Oh my gosh, in my lifetime, maybe cancer is going to be cured! Heart disease, well, that's not going to happen.” So that was really the turning point.   Pat Loehrer: When many of us started, we were just hoping that we could get patients to live a little bit longer and improve the response rate. But you took a different tack. You really looked at treating the whole patient, not just the disease. That was really a novel approach at the time. What influenced you to take that step forward? Dr. Patricia Ganz: Well, it was actually my starting– it was thought to be in a hospice ward. It would turn out it was a Sepulveda VA, not the West LA VA, but in any case, we have two VAs that are affiliated with UCLA. And it was an intermediate care ward, and there was an idea that we would in fact put our cancer patients there who had to have inpatient chemotherapy so they wouldn't be in the acute setting as well as patients who needed to travel for radiation. Actually, the West LA VA had a hospice demonstration project. This is 1978. It's really the beginning of the hospice movement in England, then in Canada, Balfour Mount at Montreal and McGill was doing this. And so I was very much influenced by, number one, most of our patients didn't live very long. And if you were at a VA Hospital, as I was at that time, you were treating patients with advanced lung cancer, advanced colon cancer, advanced prostate cancer, other GI malignancies, and lung cancer, of course. So it was really the rare patient who you would treat for curative intent.  In fact, small cell lung cancer was so exciting to be treating in a particularly limited small cell. Again, I had a lot of people who survived. We gave them chemo, radiation, whole brain radiation, etc. So that was exciting. This was before cisplatin and others were used in the treatment of lung cancer. But really, as I began to develop this ward, which I kind of thought, “Well, why should we wait just to give all the goodies to somebody in the last few weeks of life here? I'm treating some patients for cure, they're getting radiation. Some of them are getting radiation and chemo for palliation.” But it was a mixed cancer ward. And it was wonderful because I had a team that would make rounds with me every week: a pharmacist, a physiatrist, a psychologist, a social worker, a dietitian. This was in 1978 or ‘79, and the nurses were wonderful. They were really available to the patients. It wasn't a busy acute ward. If they were in pain, they would get their medication as soon as possible. I gave methadone. It was before the days of some of the newer medications, but it was long-acting. I learned how to give that. We gave Dilaudid in between if necessary. And then we had Brompton solution, that was before there was really oral morphine.  And so the idea was all of these kinds of services should really be available to patients from the time of diagnosis until death. We never knew who was going to be leaving us the next few days or who was going to be living longer and receiving curative intent. We had support groups for the patients and their families. It was a wonderful infrastructure, something that I didn't actually have at UCLA, so it was a real luxury. And if you know the VA system, the rehabilitation services are wonderful. They had dental services for patients. We had mostly World War II veterans, some Korean, and for many of these individuals, they had worked and lived a good life, and then they were going to retire and then they got cancer. So this was kind of the sadness. And it was a suburban VA, so we had a lot of patients who were in the San Fernando Valley, had a lot of family support, and it was a wonderful opportunity for me to learn how to do good quality care for patients along the continuum.  Dave Johnson: How did you assemble this team? Or was it in place in part when you arrived, or what? Nobody was thinking about this multidisciplinary approach?  Dr. Patricia Ganz: I just designed it because these were kind of the elements that were in a hospice kind of program. And I actually worked with the visiting nurses and I was part of their boards and so forth. And UCLA didn't have any kind of hospice or palliative care program at that time. But because the VA infrastructure had these staff already, I didn't have to hire them, you didn't have to bill for anything. They just became part of the team. Plus there was a psychiatrist who I ultimately began doing research with. He hired a psychologist for the research project. And so there was kind of this infrastructure of interest in providing good supportive care to cancer patients. A wonderful social worker, a wonderful psychologist, and they all saw this patient population as very needy, deserving, and they were glad to be part of a team.  We didn't call it a hospice, we called it a palliative care unit. These were just regular staff members who, as part of their job, their mission was to serve that patient population and be available. I had never been exposed to a physiatrist before. I trained at UCLA, trained and did my residency and fellowship. We didn't have physiatry. For whatever reason, our former deans never thought it was an important physical medicine, it wasn't, and still isn't, part of our system. Pat Loehrer: Many decisions we make in terms of our careers are based on singular people. Your dad, maybe, suggesting going into medicine, but was there a patient that clicked with you that said, "Listen, I want to take this different direction?" Or was it just a collection of patients that you were seeing at the VA? Is there one that you can reflect back on? Dr. Patricia Ganz: I don't know if you all remember, but there was something called Consultation Liaison Psychiatry where, in that time, the psychiatrist really felt that they had to see medical patients because there were psychological and sometimes psychiatric problems that occurred on the medical ward, such as delirium. That was very common with patients who were very sick and very toxic, which was again due to the medical condition affecting the brain. And so I was exposed to these psychiatrists who were very behaviorally oriented when I was a resident and a fellow, and they often attended our team meetings in oncology on our service, they were on the transplant service, all those kinds of things. So they were kind of like right by our side.  And when I went to the VA, the psychiatry service there also had a couple of really excellent psychiatrists who, again, were more behaviorally focused. Again, you have to really remember, bless her heart, Jimmie Holland was wonderful as a psychiatrist. She and Barrie Cassileth were the kind of early people we would see at our meetings who were kind of on the leading edge of psychosocial oncology, but particularly, Jimmie was more in a psychiatric mode, and there was a lot of focus on coping. But the people that I began to work with were more behaviorally focused, and they were kind of interested in the impact of the disease and the treatment on the patient's life and, backwards, how could managing those kinds of problems affect the well-being of the patient. And this one psychiatrist, Richard Heinrich, had gotten money from the VA, had written a grant to do an intervention study with the oncology patients who I was serving to do a group intervention for the patients and their families. But, in order to even get this grant going, he hired a project manager who was a psychologist, a fresh graduate whose name was Anne Coscarelli, and her name was Cindie Schag at that time. But she said, "I don't know much about cancer. I've got to interview patients. I've got to understand what's going on." And they really, really showed me that, by talking to the patient, by understanding what they were experiencing, they could get a better handle on what they were dealing with and then, potentially, do interventions. So we have a wonderful paper if you want to look it up. It's called the “Karnofsky Performance Status Revisited.” It's in the second issue of JCO, which we published; I think it was 1984.  Dave Johnson: In the early 90s, you relocated back to UCLA. Why would you leave what sounds like the perfect situation to go back to a site that didn't have it? Dr. Patricia Ganz: Okay, over that 13 years that I was at the VA, I became Chief of the Division of Hem-Onc. We were actually combined with a county hospital. It was a wonderful training program, it was a wonderful patient population at both places. And we think that there are troubles in financing health care now, well, there were lots of problems then. Medicaid came and went. We had Reagan as our governor, then he became president, and there were a lot of problems with people being cared for. So it was great to be at the VA in the county, and I always felt privileged. I always had a practice at UCLA, which was a half-day practice, so I continued there, and I just felt great that I could practice the same wherever I was, whether it was in a public system, veteran system, or in the private system.   But what happened was, I took a sabbatical in Switzerland, '88 to '89. I worked with the Swiss International Breast Cancer Consortium group there, but it was really a time for me to take off and really learn about quality of life assessment, measurement, and so forth. When I came back, I basically said, "I want to make a difference. I want to do something at a bigger arena." If I just continue working where I am, it's kind of a midlife crisis. I was in my early 40s, and my office was in the San Fernando Valley at the VA, but my home was in West Los Angeles. One day I was in UCLA, one day I was at the VA, one day I was at the county, it was like, "Can I practice like this the next 20 years? I don't know that I can do this. And I really want to have some bigger impact.” So I went to Ellen Gritz who was my predecessor in my current position, and I was doing my NCI-funded research at UCLA still, and I said, “Ellen, I really would like to be able to do research full time. I really want to make a difference. Is there anything available? Do you know of anything?" And she said, "Well, you know, we're actually recruiting for a position that's joint between the School of Public Health and the Cancer Center. And oh my goodness, maybe I can compete for that, so that's what I did. And it was in what was then the department called Health Services, it's now called Health Policy and Management. I applied, I was competing against another person who I won't name, but I got the position and made that move.  But again, it was quite a transition because I had never done anything in public health, even though UCLA had a school of public health that was right adjacent to the medical school. I had had interactions with the former dean, Lester Breslow, who I actually took an elective with when I was a first-year medical student on Community Medicine. So it kind of had some inklings that, of what I was interested in. I had actually attendings in my medical clinic, Bob Brook, a very famous health policy researcher, Sheldon Greenfield. So I'd been exposed to a lot of these people and I kind of had the instinctive fundamentals, if you will, of that kind of research, but hadn't really been trained in it. And so it was a great opportunity for me to take that job and really learn a lot and teach with that.  And then took, part of my time was in the cancer center with funding from the core grant. And then, within a year of my taking this position, Ellen left and went to MD Anderson, so all of a sudden I became director of that whole population science research group. And it was in the early ‘90s, had to scramble to get funding, extramural funding. Everybody said to me, "How could you leave a nearly full-time position at the VA for a soft money position?" But, nevertheless, it worked out. And it was an exciting time to be able to go into a new career and really do things that were not only going to be in front and center beneficial to patients, but to a much larger group of patients and people around the world.  Pat Loehrer: Of all the work that you have done, what one or two things are you most proud of in terms of this field? Dr. Patricia Ganz: Recognizing the large number of people who are surviving cancer. And I think today we even have a more exciting part of that. I mean, clearly, many people are living long-term disease-free with and without sequelae of the disease. But we also have this new group of survivors who are living on chronic therapy. And I think the CML patients are kind of the poster children for this, being on imatinib or other newer, targeted agents over time, living with cancer under control, but not necessarily completely gone. And then melanoma with the immunotherapy, lung cancer, all of these diseases now being converted to ones that were really fatal, that are now enjoying long-term treatment.   But along with that, we all know, is the financial toxicity, the burdens, and even the ongoing symptoms that patients have. So the fact that we all call people survivors and think about people from the time of diagnosis as potentially being survivors, I think was very important. And I would say that, from the clinical side, that's been very important to me. But all of the work that I was able to do with the Institute of Medicine, now the National Academy of Medicine, the 2013 report that we wrote on was a revisit of Joe Simone's quality of care report, and to me was actually a very pivotal report. Because in 2013, it looked like our health care system was in crisis and the delivery of care. We're now actually doing a National Cancer Policy Forum ten-year follow-up of that report, and many of the things that we recommended, surprisingly, have been implemented and are working on. But the healthcare context now is so much more complicated.  Again, with the many diseases now becoming rare diseases, the cost of drugs, the huge disparities, even though we have access through the Affordable Care Act and so forth, there's still huge disparities in who gets care and treatment. And so we have so many challenges. So for me, being able to engage in the policy arena and have some impact, I think has been also very important to me. Dave Johnson: 20 years ago, the topic of survivorship was not that common within ASCO, and you led a 2004 task force to really strengthen that involvement by that organization, and you also were a founding member of the National Coalition for Cancer Survivorship. I wonder if you might reflect on those two activities for us for a moment. Dr. Patricia Ganz: In 1986, Fitzhugh Mullen, who in 1985 had written a really interesting special article for the New England Journal called "Seasons of Survivorship" - he was a young physician when he was found to have a mediastinal germ cell tumor and got very intensive chemotherapy and radiation therapy and survived that, but realized that there was no place in the healthcare system where he could turn to to get his questions answered, nor get the kind of medical care that was needed, and really wrote this very important article. He then, being somebody who was also kind of policy-oriented and wanting to change the world, and I would say this was a group of us who, I think went to college during the Vietnam era - so did Fitz - and we were all kind of restless, trying to see how we could make a difference in the world and where it was going.   And so he had this vision that he was going to almost develop an army of survivors around the country who were going to stand up and have their voices heard about what was going on. Of course, most people didn't even know they were a survivor. They had cancer treatment, but they didn't think about themselves as a survivor. And so he decided to get some people together in Albuquerque, New Mexico, through a support group that he had worked with when he was in the Indian Health Service in New Mexico. And there were various people from the American Cancer Society, from other support organizations, social workers, and a couple of us who are physicians who came to this meeting, some Hodgkin survivors who had been treated at Stanford and were now, including a lawyer, who were starting to do long term late effects work. And we gathered together, and it was a day and a half, really, just kind of trying to figure out how could a movement or anything get oriented to try and help patients move forward.  So that's how this was founded. And they passed the hat. I put in a check for $100, and that was probably a lot of money at that time, but I thought, well, this is a good investment. I'll help this organization get started. And that was the start. And they kind of ran it out of Living Beyond Cancer in Albuquerque for a few years. But then Fitz, who was in the Washington, DC. area decided they weren't going to be able to get organizations all over the country organized to do this, and they were going to have to do some lobbying. So Ellen Stovall, who was a Hodgkins survivor living in the Washington area, beginning to do policy work in this area, then became the executive director and took the organization forward for many years and championed this, got the Office of Cancer Survivors established at the NCI in the 1990s, and really did a lot of other wonderful work, including a lot of the work at the Institute of Medicine. She was very involved with the first Quality of Care report and then ultimately the survivorship report, the Lost and Transition report in 2005, 2006, I was on that committee. So that was really how things were evolving.  And by that time, I was also on the ASCO board, 2003 to 2006. And so all of these things were kind of coming together. We had 10 million survivors. That was kind of an important note and a lot of diseases now - lymphoma, breast cancer, multi-agent therapy had certain benefits, but obviously toxicities. We lived through the horrible time of high-dose chemotherapy and transplant for breast cancer in the ‘90s, which was a problem, but we saw a lot of toxicities after that. And so there were people living after cancer who now had sequelae, and the children obviously had been leading the way in terms of the large number of childhood cancer survivors. So this was this idea that the children were kind of the canary in the coal mine. We saw them living 20, 30 years later after their cancer diagnosis, and we were now beginning to see adults living 10, 15, 20 years later, and we needed to think about these long-term and late effects for them as well. Dave Johnson: I'm glad you mentioned Fitz's article in the New England Journal that still resonates today, and if listeners have not read it, "Seasons of Survivorship" is a worthwhile five-minute read.  What do you think the most pressing issues and challenges in cancer survivorship care today?  Dr. Patricia Ganz: Many people are cured with very little impact. You can think of somebody with T1 breast cancer maybe needing endocrine therapy for five years, and lumpectomy radiation. That person's probably not going to have a lot that they're going to be worried about. But if they're a young breast cancer patient, say they're 35 or 40, you're going to get five years of ovarian suppression therapy. You're going to be put into acute menopause. You're going to lose bone density. You're going to have cardiac risk acceleration. You may have cognitive changes. You may have also problems with cognitive decline later. I mean, all of these things, the more intense treatments are associated, what we're really thinking about is accelerated aging. And so a lot of what I've been studying the last 20-25 years in terms of fatigue and cognitive difficulties are related to neuroinflammation and what happens when somebody has intensive systemic therapy and that accelerated process that's, again, not everyone, but small numbers of patients, could be 10-15-20%. So I worry a lot about the young patients. So I've been very focused on the young adult population who are treated intensively for lymphoma, leukemia, and breast. And that's, I think, something that we need to be looking out for.  The other thing is with the newer therapies, whether it's immunotherapy or some of the targeted therapies, we just don't know what the late effects are going to be. Where we're very schooled now in what the late effects of radiation, chemo, and surgery could be for patients, we just don't know. And another wonderful part of my career has been to be able to do quality-of-life studies within the Clinical Trials Network. I've been affiliated with NSABP, I was SWOG previously, but NSABP is now NRG Oncology doing patient-reported outcomes and looking at long-term outcomes in clinical trials. And I think we're going to need this for all of these new agents because we have no idea what the long-term toxicities are going to be. And even though it's amazing to have people surviving where they wouldn't have been, we don't know what the off-target long-term effects might be. So that's a real challenge right now for survivorship.  And the primary care doctors who we would want to really be there to orchestrate the coordinated care for patients to specialists, they are a vanishing breed. You could read the New England Journal that I just read about the challenges of the primary care physician right now and the overfilled inbox and low level of esteem that they're given in health systems. Where are we going to take care of people who really shouldn't be still seeing the oncologist? The oncologist is going to be overburdened with new patients because of the aging of the population and the many new diagnoses. So this is our new crisis, and that's why I'm very interested in what we're going to be looking at in terms of a ten-year follow-up report to the 2013 IOM report. Dave Johnson: The industry-based trials now are actually looking at longer-term treatment. And the trials in which interest is cancer, we cut it down from two years of therapy down to nine weeks of therapy, looking at minimizing therapy. Those are difficult trials to do in this climate today, whereas the industry would just as soon have patients on for three to five years worth of therapy as opposed to three to five months. Talk a little about those pressures and what we should be doing as a society to investigate those kinds of therapies and minimizing treatments. Dr. Patricia Ganz: Minimizing treatments, this is the place where the government has to be, because we will not be able to do these de-escalation studies. Otherwise, there will be countries like the UK, they will be able to do these studies, or other countries that have national health systems where they have a dual purpose, if you will, in terms of both financing health care and also doing good science. But I think, as I've seen it, we have a couple of de-escalation trials for breast cancer now in NRG Oncology, which is, again, I think, the role that the NCTN needs to be playing. But it's difficult for patients. We all know that patients come in several breeds, ones who want everything, even if there's a 1% difference in benefit, and others who, “Gee, only 1 out of 100 are going to benefit? I don't want that.” I think that's also the challenge. And people don't want to be denied things, but it's terrible to watch people go through very prolonged treatments when we don't know that they really need it for so long.  Dave Johnson: Pat and I both like to read. I'm wondering if there's something you've read recently that you could recommend to us. Dr. Patricia Ganz: It's called A Gentleman in Moscow by Amor Towles. I do like to read historical fiction. This one is about a count at the time of the Bolshevik Revolution who then gets imprisoned in a hotel in Moscow and how constrained his life becomes, but how enriched it is and follows him over really a 50-year period of time and what was happening in the Soviet Union during that time. And of course, with the war in Ukraine going on, very interesting. Of course, I knew the history, but when you see it through the drama of a personal story, which is fictional, obviously it was so interesting.   My husband escaped from Czechoslovakia. He left in '66, so I had exposure to his family and what it was like for them living under communism. So a lot of that was interesting to me as well.  Dave Johnson: Thank you for joining us. It's been a wonderful interview and you're to be congratulated on your accomplishments and the influence you've had on the oncology world.  We also want to thank our listeners of Oncology, Etc., and ASCO Educational Podcast where we will talk about oncology, medicine and beyond. So if you have an idea for a topic or a guest you'd like us to interview, by all means, email us at education@asco.org. To stay up to date with the latest episodes and explore other ASCO educational content, please visit education.asco.org. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

*Note, we aware part of the video froze; that's life!    RESEARCH! - Dr. Helbig gave a killer presentation today… at Stanford.  It was so cool to see SYNGAP1 mentioned. “Deciphering the Epilepsy Phenome – Understanding Longitudinal disease trajectories and outcomes” it showed how much data you can get form EHRs, ciitizen and NHS.  We need them all.  Sign up for Ciitizen!  https://www.ciitizen.com/SYNGAP1/ - SRF Supported work out of Huganir's Lab is on BioRx! https://www.biorxiv.org/content/10.1101/2023.08.06.552111v1.full.pdf - Grants due on 9/1, already seeing good stuff. https://www.syngapresearchfund.org/professionals/grants/how-to-apply   VOLUNTEER SITE IS UP - https://www.syngapresearchfund.org/volunteer-with-syngap-research-fund   WEBINARS ARE A VALUABLE RESOURCE - https://www.syngapresearchfund.org/families/resources/all-webinars/webinars - Yesterday, Dr. Underbakk, Previously with Dr. Courtney   NPR ARTICLE INCLUDING JACKIE KANCIR - https://wpln.org/post/episodes/the-cost-of-care-for-disabilities-and-chronic-illness   SYNGAP STORIES Ashley Frye is killing it.  Suzanne Jones just did an episode.  The CHOP team listens, so do clinicians.  Call Ashley and share your story.   COMPANY UPDATES - Stoke had great news - https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-reports-second-quarter-financial-results-2 - Praxis also having good results - https://investors.praxismedicines.com/news-releases/news-release-details/praxis-precision-medicines-provides-corporate-update-and-9 - Have not heard from RegEl or Ionis.   EVENTS - Getting ready for the Soiree - August 26th. - Cannonball set for October 4-6 - SRF SYNGAP1 CONFERENCE      - Register, book etc. https://www.syngapresearchfund.org/professionals/syngap1-roundtable-2023-syngap-research-fund     - Watch #s10e109 https://youtu.be/to8SAwdzCmg   BIOMARKERS NEED BIOSAMPLES AND EEGS - Combined Brain collections are great Dr. TJB met our very own Pavel this weekend!  Plasma, plasma, plasma. - UCLA Study is moving forward for EEG collection.  Contact Declan via study page.   Upcoming times and places to do biosamples, thanks you Corey we are at 18 Syngapians and 21 Siblings.  KEEP GOING - GLUT1 Deficiency, August 26th, 9am-5pm (Embassy Suites, 13700 Conference Center Drive South, Noblesville, IN 46060) - IRF2BPL Foundation, Sept 22nd-23rd 2023 (Home 2 Suites by Hilton, 7145 Liberty Centre Drive, Liberty Township, OH 45069, 513-644-2207) - KCNQ2 Cure Alliance Conference, Sept 29th-30th 2023 (Hilton Hotel Chicago 300 E Ohio St, Chicago, IL 60611) - NARS1 Conference, October 1st, 9am-5pm (13550 Commerce Blvd Rogers, MN 55374) - Prader-Willi Syndrome/USP7 Foundation, October 5-7 (1672 Lawrence St, Denver, CO 80202) - TBRS Community, Oct 12th-14th 2023 (Morgan's Wonderland, 5223 David Edwards Dr, San Antonio, TX 78233) - COMBINEDBrain Meeting, Oct 15th-16th 2023 (Washington DC) - FAM177A1, Oct 29th 2023, 9am-5pm (2737 77th Ave Se Suite 101 Mercer Island, WA 98040) - ADNP Syndrome, Oct 30th-Nov 1st 2023 (Los Angeles, CA) - SYNGAP1 Research Fund, Dec 1st-3rd 2023 (8978 International Drive Orlando, FL, 32819) —--- CONFERENCE  Registration link: https://Syngap.Fund/Orlando   Hotels ASAP: https://Syngap.Fund/2023hotel  Shirts https://www.bonfire.com/srf-syngap1-conference-2023/    Volunteer with SRF! Info@SyngapResearchFund.org    This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here  - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts:  https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 111 of #Syngap10 - August 12, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat

*Note, we are aware part of the video froze; that's life!  RESEARCH! - Dr. Helbig gave a killer presentation today… at Stanford.  It was so cool to see SYNGAP1 mentioned. “Deciphering the Epilepsy Phenome – Understanding Longitudinal disease trajectories and outcomes” it showed how much data you can get form EHRs, ciitizen and NHS.  We need them all.  Sign up for Ciitizen!  https://www.ciitizen.com/SYNGAP1/ - SRF Supported work out of Huganir's Lab is on BioRx! https://www.biorxiv.org/content/10.1101/2023.08.06.552111v1.full.pdf - Grants due on 9/1, already seeing good stuff. https://www.syngapresearchfund.org/professionals/grants/how-to-apply VOLUNTEER SITE IS UP - https://www.syngapresearchfund.org/volunteer-with-syngap-research-fund WEBINARS ARE A VALUABLE RESOURCE - https://www.syngapresearchfund.org/families/resources/all-webinars/webinars - Yesterday, Dr. Underbakk, Previously with Dr. Courtney NPR ARTICLE INCLUDING JACKIE KANCIR - https://wpln.org/post/episodes/the-cost-of-care-for-disabilities-and-chronic-illness SYNGAP STORIESAshley Frye is killing it.  Suzanne Jones just did an episode.  The CHOP team listens, so do clinicians.  Call Ashley and share your story. COMPANY UPDATES - Stoke had great news - https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-reports-second-quarter-financial-results-2 - Praxis also having good results - https://investors.praxismedicines.com/news-releases/news-release-details/praxis-precision-medicines-provides-corporate-update-and-9 - Have not heard from RegEl or Ionis. EVENTS - Getting ready for the Soiree - August 26th. - Cannonball set for October 4-6 - SRF SYNGAP1 CONFERENCE      - Register, book etc. https://www.syngapresearchfund.org/professionals/syngap1-roundtable-2023-syngap-research-fund     - Watch #s10e109 https://youtu.be/to8SAwdzCmg BIOMARKERS NEED BIOSAMPLES AND EEGS - Combined Brain collections are great Dr. TJB met our very own Pavel this weekend!  Plasma, plasma, plasma. - UCLA Study is moving forward for EEG collection.  Contact Declan via study page. Upcoming times and places to do biosamples, thanks you Corey we are at 18 Syngapians and 21 Siblings.  KEEP GOING - GLUT1 Deficiency, August 26th, 9am-5pm (Embassy Suites, 13700 Conference Center Drive South, Noblesville, IN 46060) - IRF2BPL Foundation, Sept 22nd-23rd 2023 (Home 2 Suites by Hilton, 7145 Liberty Centre Drive, Liberty Township, OH 45069, 513-644-2207) - KCNQ2 Cure Alliance Conference, Sept 29th-30th 2023 (Hilton Hotel Chicago 300 E Ohio St, Chicago, IL 60611) - NARS1 Conference, October 1st, 9am-5pm (13550 Commerce Blvd Rogers, MN 55374) - Prader-Willi Syndrome/USP7 Foundation, October 5-7 (1672 Lawrence St, Denver, CO 80202) - TBRS Community, Oct 12th-14th 2023 (Morgan's Wonderland, 5223 David Edwards Dr, San Antonio, TX 78233) - COMBINEDBrain Meeting, Oct 15th-16th 2023 (Washington DC) - FAM177A1, Oct 29th 2023, 9am-5pm (2737 77th Ave Se Suite 101 Mercer Island, WA 98040) - ADNP Syndrome, Oct 30th-Nov 1st 2023 (Los Angeles, CA) - SYNGAP1 Research Fund, Dec 1st-3rd 2023 (8978 International Drive Orlando, FL, 32819) —--- CONFERENCE  Registration link: https://Syngap.Fund/Orlando   Hotels ASAP: https://Syngap.Fund/2023hotel  Shirts https://www.bonfire.com/srf-syngap1-conference-2023/  Volunteer with SRF! Info@SyngapResearchFund.org  This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here  - https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts:  https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 111 of #Syngap10 - August 12, 2023 #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GeneChat --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

On this episode of Biotalk, Locust Walk‘s Geoff Meyerson welcomes Onaiza Cadoret-Manier, Executive Vice President, Chief Global Product Strategy & Operations Officer at Ionis Pharmaceuticals to the podcast. With 30 years of experience in life sciences, Onaiza is a member of Ionis' executive leadership team, overseeing the company's portfolio planning, global product strategy, medical affairs, […]

On this episode of Biotalk, Locust Walk‘s Geoff Meyerson welcomes Onaiza Cadoret-Manier, Executive Vice President, Chief Global Product Strategy & Operations Officer at Ionis Pharmaceuticals to the podcast. With 30 years of experience in life sciences, Onaiza is a member of Ionis' executive leadership team, overseeing the company's portfolio planning, global product strategy, medical affairs, market access, and commercial strategy and operations functions.   During the episode, Onaiza discusses her journey into biotech, her tenure at Ionis and challenges overcome while shifting from an R&D to commercialization focus, and her perspective and outlook on the biotech market.  We invite you to listen to our podcast and read our RNA Therapeutics Landscape Overview. Subscribe or follow Biotalk on Apple Podcasts | Spotify.  Timestamps:    1:12: How did you find yourself in the biotech industry?    2:12: Prior to starting at Ionis, you held roles at Grail, Genentech, Pfizer and Amylin. What is a key takeaway you have from each of those experiences?  6:12: What were some challenges you had to overcome when shifting from an R&D focus to commercialization? How has that evolved over time with Ionis?  11:16: Do you have any advice for how to think about the process for picking the best targets for a company, especially if they have differing levels of resource?  13:35: What excites you about the pipeline or innovations that you're seeing either internal to Ionis or externally?  16:54: Is it true that Ionis is looking to both buy and sell?  18:28: COVID had a profound effect on the industry, which experienced a huge run followed by an even bigger downturn. What's your perspective on the industry today? What's your outlook for 2023?   22:39: Despite all of these headwinds, we remain highly optimistic about the future of biotech.  Are you optimistic as well? 

This week, Jeremy talks to Dr. Paul Larkin, director of research at The ALS Association, and Dr. Frank Bennett, Chief Scientific Officer at Ionis and a pioneer in the field of antisense oligonucleotide research, about the FDA's approval of tofersen and the future of ALS drug development. To learn more about why the FDA's decision on tofersen matters to everyone, check out: https://www.als.org/blog/tofersen-approved-sod1-als For more information on antisense technology go to: https://www.als.org/research/research-we-fund/scientific-focus-areas/genetics/antisense-therapy-for-alsThis episode is brought to you The ALS Association in partnership with CitizenRacecar. 

This episode is proudly sponsored by our partner, Alnylam Pharmaceuticals, the leading RNAi therapeutics company. When Stan Crooke ran Ionis and John Maraganore ran Alnylam, they were partners that turned into rivals — and not always friendly ones — as they persevered to pursue an entirely new therapeutic space; RNA-targeted drug discovery and development. Now, the pair of drug discovery titans have united once again in support of Dr. Crooke's n-Lorem Foundation—working to provide personalized medicines to the rarest of rare disease patients (nano-rare) using the antisense oligonucleotide (ASO) technology Stan led the creation of at Ionis. In this episode, Stan has a conversation with Dr. John Maraganore about John's past, their former rivalry, and the optimism shared between the two with respect to a better future for nano-rare patients.On This Episode We Discuss:- Being a dream merchant and driving a dream into a real therapeutic platform- Founding of Regulus and the synergy between Ionis and Alnylam throughout the years- What happens when two very competitive CEO-scientists have competing drugs- Overcoming their differences- Giving hope to a patient and their family with nano-rare diseases is powerful- Saving the world one life at a time- Bringing ASO and RNAi technologies together to collaboratively help nano-rare patients- A sustainable non-profit model?- Hope – a powerful thing to lose and an important thing to recover

This month on Episode 47 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the March 31 issue of Circulation Research. We'll also provide an overview of the Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease published in the April 14 issue. Finally, this episode features an interview with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   Article highlights:   Shi, et al. LncRNAs Regulate SMC Phenotypic Transition   Chen, et al. Bilirubin Stabilizes Atherosclerotic Plaque   Subramaniam, et al. Mapping Non-Obvious cAMP Nanodomains by Proteomics   Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease   Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to share three articles selected from our March 31st issue of Circulation Research and give you a quick summary of our April 14th Compendium. I'm also excited to speak with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   So first the highlights. The first article we're going to discuss is Discovery of Transacting Long Noncoding RNAs that Regulates Smooth Muscle Cell Phenotype. This article's coming from Stanford University and the laboratory of Dr Thomas Quertermous. Smooth muscle cells are the major cell type contributing to atherosclerotic plaques. And in plaque pathogenesis, the cells can undergo a phenotypic transition whereby a contractile smooth muscle cell can trans differentiate into other cell types found within the plaque, such as macrophage-like cells, osteoblast-like cells and fibroblast-like cells. These transitions are regulated by a network of genetic and epigenetic mechanisms, and these mechanisms govern the risk of disease.   The involvement of long non-coding RNAs, or Lnc RNAs as they're called, has been increasingly identified in cardiovascular disease. However, smooth muscle cell Lnc RNAs have not been comprehensively characterized and the regulatory role in the smooth muscle cell state transition is not thoroughly understood. To address this gap, Shi and colleagues created a discovery pipeline and applied it to deeply strand-specific RNA sequencing from human coronary artery smooth muscle cells that were stressed with different disease related stimuli. Subsequently, the functional relevancy of a few novel Lnc RNAs was verified in vitro.   From this pipeline, they identified over 4,500 known and over 13,000 unknown or previously unknown Lnc RNAs in human coronary artery smooth muscle cells. The genomic location of these long noncoding RNAs was enriched near coronary artery disease related transcription factor and genetic loci. They were also found to be gene regulators of smooth muscle cell identity. Two novel Lnc RNAs, ZEB-interacting suppressor or ZIPPOR and TNS1-antisense or TNS1-AS2, were identified by the screen, and this group discovered that the coronary artery disease gene, ZEB2, which is a transcription factor in the TGF beta signaling pathway, is a target for these Lnc RNAs. These data suggest a critical role for long noncoding RNAs in smooth muscle cell phenotypic transition and in human atherosclerotic disease.   Cindy St. Hilaire:              The second article I want to share is titled Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency. This article is coming from the Heart Research Institute and the corresponding author is Roland Stocker. The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin, a byproduct of heme catabolism, is inversely associated with risk of cardiovascular disease, but the link between bilirubin and atherosclerosis is unknown.   Chen et el addressed this gap by crossing a bilirubin knockout mice to a atherosclerosis prone APOe knockout mouse. Chen et el addressed this gap by crossing the bilirubin knockout mouse to the atherosclerosis-prone APOE knockout mouse, and used the tandem stenosis model of plaque instability to address this question. Compared with their litter mate controls, bilirubin-APOE double knockouts showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia. And they had higher atherosclerotic plaque burden.   Hemeatabolism was increased in unstable plaques compared with stable plaques in both of these groups as well as in human coronary arteries. In mice, the bilirubin deletion selectively destabilized unstable plaques and this was characterized by positive arterial remodeling and increased cap thinning, intra plaque hemorrhage, infiltration of neutrophils and MPO activity. Subsequent proteomics analysis confirmed bilirubin deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils and associated oxidative stress in the unstable plaque. Thus, bilirubin deficiency generates a pro atherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaques, thereby providing a link between bilirubin and cardiovascular disease risk.   Cindy St. Hilaire:              The third article I want to share is titled Integrated Proteomics Unveils Regulation of Cardiac Monocyte Hypertrophic Growth by a Nuclear Cyclic AMP Nano Domain under the Control of PDE3A. This study is coming from the University of Oxford in the lab of Manuela Zaccolo. Cyclic AMP is a critically important secondary messenger downstream from a myriad of signaling receptors on the cell surface. Signaling by cyclic AMP is organized in multiple distinct subcellular nano domains, regulated by cyclic AMP hydrolyzing phosphodiesterases or PDEs.   The cardiac beta adrenergic signaling has served as the prototypical system to elucidate this very complex cyclic AMP compartmentalization. Although studies in cardiac monocytes have provided an understanding of the location and the properties of a handful of these subcellular domains, an overview of the cellular landscape of the cyclic AMP nano domains is missing.   To understand the nanodynamics, Subramanian et al combined an integrated phospho proteomics approach that took advantage of the unique role that individual phosphodiesterases play in the control of local cyclic AMP. They combined this with network analysis to identify previously unrecognized cyclic AMP nano domains associated with beta adrenergic stimulation. They found that indeed this integrated phospho proteomics approach could successfully pinpoint the location of these signaling domains and it provided crucial cues to determine the function of previously unknown cyclic AMP nano domains.   The group characterized one such cellular compartment in detail and they showed that the phosphodiesterase PDE3A2 isoform operates in a nuclear nano domain that involves SMAD4 and HDAC1. Inhibition of PDE3 resulted in an increased HDAC1 phosphorylation, which led to an inhibition of its deacetylase activity, and thus derepression of gene transcription and cardiac monocyte hypertrophic growth. These findings reveal a very unique mechanism that explains the negative long-term consequences observed in patients with heart failure treated with PDE3 inhibitors.   Cindy St. Hilaire:              The April 14th issue is our compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease. Dr Heidi Noels from the University of Aachen is our guest editor of the 11 articles in this issue. Chronic kidney disease is defined by kidney damage or a reduced kidney filtration function. Chronic kidney disease is a highly prevalent condition affecting over 13% of the population worldwide and its progressive nature has devastating effects on patient health. At the end stage of kidney disease, patients depend on dialysis or kidney transplantation for survival. However, less than 1% of CKD patients will reach this end stage of chronic kidney disease. Instead, most of them with moderate to advanced chronic kidney disease will prematurely die and most often they die from cardiovascular disease. And this highlights the extreme cardiovascular burden patients with CKD have.   The titles of the articles in this compendium are the Cardio Kidney Patient Epidemiology, Clinical Characteristics, and Therapy by Nicholas Marx, the Innate Immunity System in Patients with Cardiovascular and Kidney Disease by Carmine Zoccali et al. NETs Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney disease by Yvonne Doering et al. Accelerated Vascular Aging and Chronic Kidney Disease, The Potential for Novel Therapies by Peter Stenvinkel et al. Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients with Chronic Kidney Disease by Heidi Noels et al. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease by Claudia Goettsch et al. Fibrosis in Pathobiology of Heart and Kidney From Deep RNA Sequencing to Novel Molecular Targets by Raphael Kramann et al. Cardiac Metabolism and Heart Failure and Implications for Uremic Cardiomyopathy by P. Christian Schulze et al. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease by Michael Burnier et al. Role of the Microbiome in Gut, Heart, Kidney crosstalk by Griet Glorieux et al, and Use of Computation Ecosystems to Analyze the Kidney Heart Crosstalk by Joachim Jankowski et al.   These reviews were written by leading investigators in the field, and the editors of Circulation Research hope that this comprehensive undertaking stimulates further research into the path flow of physiological kidney-heart crosstalk, and on comorbidities and intra organ crosstalk in general.   Cindy St. Hilaire:              So for our interview portion of the episode I have with me Dr Elizabeth Tarling and Dr Bethan Clifford. And Dr Tarling is an associate professor in the Department of Medicine in cardiology at UCLA, and Dr Clifford is a postdoctoral fellow with the Tarling lab. And today we're going to be discussing their manuscript that's titled, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels. So thank you both so much for joining me today.   Elizabeth Tarling:             Thank you for having us.   Bethan Clifford:               Yeah, thanks for having us. This is exciting.   Cindy St. Hilaire:              I guess first, Liz, how did you get into this line of research? I guess, before we get into that, I should disclose. Liz, we are friends and we've worked together in the ATVB Women's Leadership Committee. So full disclosure here, that being said, the editorial board votes on these articles, so it's not just me picking my friends. But it is great to have you here. So how did you enter this field, I guess, briefly?   Elizabeth Tarling:             Yeah, well briefly, I mean my training right from doing my PhD in the United Kingdom in the University of Nottingham has always been on lipid metabolism, lipoprotein biology with an interest in liver and cardiovascular disease. So broadly we've always been interested in this area and this line of research. And my postdoctoral research was on atherosclerosis and lipoprotein metabolism. And this project came about through a number of different unique avenues, but really because we were looking for regulators of LDL biology and plasma LDL cholesterol, that's sort of where the interest of the lab lies.   Cindy St. Hilaire:              Excellent. And Bethan, you came to UCLA from the UK. Was this a topic you were kind of dabbling in before or was it all new for you?   Bethan Clifford:               It was actually all completely new for me. So yeah, I did my PhD at the same university as Liz and when I started looking for postdocs, I was honestly pretty adamant that I wanted to stay clear away from lipids and lipid strategy. And then it wasn't until I started interviewing and meeting people and I spoke to Liz and she really sort of convinced me of the excitement and that the interest and all the possibilities of working with lipids and well now I won't go back, to be honest.   Cindy St. Hilaire:              And now here you are. Well-   Bethan Clifford:               Exactly.   Cindy St. Hilaire:              ... congrats on a wonderful study. So LDLR, so low density lipoprotein receptor, it's a major determinant of plasmid LDL cholesterol levels. And hopefully most of us know and appreciate that that is really a major contributor and a major risk for the development of atherosclerosis and coronary artery disease. And I think one thing people may not really appreciate, which your study kind of introduces and talks about nicely, is the role of the liver, right? And the role of receptor mediated endocytosis in regulating plasma cholesterol levels. And so before we kind of chat about the nitty-gritty of your study, could you just give us a brief summary of these key parts between plasma LDL, the LDL receptor and where it goes in your body?   Elizabeth Tarling:             Yeah. So the liver expresses 70% to 80% of the body's LDL receptor. So it's the major determinant of plasma lipoprotein plasma LDL cholesterol levels. And through groundbreaking work by Mike Brown and Joe Goldstein at the University of Texas, they really define this receptor mediated endocytosis by the liver and the LDL receptor by looking at patients with familial hypercholesterolemia. So those patients have mutations in the LDL receptor and they either express one functional copy or no functional copies of the LDL receptor and they have very, very large changes in plasma LDL cholesterol. And they have severe increases in cardiovascular disease risk and occurrence and diseases associated with elevated levels of cholesterol within the blood and within different tissues. And so that's sort of how the liver really controls plasma LDL cholesterol is through this receptor mediated endocytosis of the lipoprotein particle.   Cindy St. Hilaire:              There's several drugs now that can help regulate our cholesterol levels. So there's statins which block that rate limiting step of cholesterol biosynthesis, but there's this new generation of therapies, the PCSK9 inhibitors. And can you just give us a summary or a quick rundown of what are those key differences really? What is the key mechanism of action that these therapies are going after and is there room for more improvement?   Bethan Clifford:               Yeah, sure. So I mean I think you've touched on something that's really key about the LDR receptor is that it's regulated at so many different levels. So we have medications available that target the production of cholesterol and then as you mentioned this newer generation of things like PCSK9 inhibitors that sort of try and target LDL at the point of clearance from the plasma.   And in response to your question of is there room for more regulation, I would say that given the sort of continual rate of increased cholesterol in the general population and the huge risks associated with elevated cholesterol, there's always capacity for more to improve that and sort of generally improve the health of the population. And what we sort of found particularly exciting about RNF130 is that it's a distinct pathway from any of these regulatory mechanisms. So it doesn't regulate the level of transcription, it doesn't regulate PCSK9. Or in response to PCSK9, it's a completely independent pathway that could sort of improve or add to changes in cholesterol.   Cindy St. Hilaire:              So your study, it's focusing on the E3 ligase, RNF130. What is an E3 ligase, and why was this particular one of interest to you? How did you come across it?   Elizabeth Tarling:             is predTates Bethan joining the lab. This is, I think, again for the listeners and those people in training, I think it's really important to note this project has been going in the lab for a number of years and has really... Bethan was the one who came in and really took charge and helped us round it out. But it wasn't a quick find or a quick story. It had a lot of nuances to it. But we were interested in looking for new regulators of LDL cholesterol and actually through completely independent pathways we had found the RNF130 locus as being associated with LDL cholesterol in animals. And then it came out in a very specific genome-wide association study in the African American care study, the NHLBI care study. And so really what we started looking at, we didn't even know what it was.   Elizabeth Tarling:             So we asked ourselves, well what is this gene? What is this protein? And it's RNF, so that's ring finger containing protein 130 and ring stands for really interesting new gene. Somebody came up with the glorious name. But proteins that contain this ring domain are very characteristic and they are E3 ubiquitin ligases. And so they conjugate the addition of ubiquitin to a target protein and that signals for that protein to either be internalized and/or degraded through different decorative pathways within the cell. And so we didn't land on it because we were looking at E3 ligases, we really came at it from an LDL cholesterol perspective. And it was something that we hadn't worked on before and the study sort of blossomed from there.   Cindy St. Hilaire:              That's amazing and a beautiful, but also, I'm sure, heartbreaking story because these long projects are just... They're bears. So what does this RNF130 do to LDLR? What'd you guys find?   Bethan Clifford:               As Liz said, this is a long process, but one of the key factors of RNF130 is it's structurally characteristically looked like E3 ligase. So the first thing that Liz did and then I followed up with in the lab is to see is this E3 ligase ubiquitinating in vitro. And if it is going to ubiquitinate, what's it likely to regulate that might cause changes in plasma cholesterol that would explain these human genetic links that we saw published at the same time.   And so because the LDL cholesterol is predominantly regulated by the LDL receptor and the levels of it at the surface of the parasites in the liver, the first question we wanted to see is does RNF130 interact in any way with that pathway? And I'm giving you the brief view here of the LDL receptor. We obviously tested lots of different receptors. We tested lots of different endocytose receptors and lipid regulators, but the LDL receptor is the one that we saw could be ubiquitinated by RNF130 in vitro. And so then we wanted to sort of go on from there and establish, okay, if this E3 ubiquitin ligase, is it regulating LDL receptor? What does that mean in an animal context in terms of regulating LDL cholesterol?   Cindy St. Hilaire:              Yeah, and I guess we should also explain, ubiquitination, in terms of this receptor, and I guess related to Goldstein and Brown and receptor mediated endocytosis, like what does that actually mean for the liver cell and the cholesterol in the LDLR that is binding the receptor?   Bethan Clifford:               So yes, ubiquitination is a really common regulatory mechanism actually across all sorts of different cells, all sorts of different receptors and proteins. And basically what it does is it signals for degradation of a protein. So a ubiquitin molecule is conjugated to its target such as in our case the LDL receptor and that ubiquitin tells the cell that this protein is ready for proteasomal degradation. And that's just one of the many things ubiquitination can do. It can also signal for a trafficking event, it can signal for a protein to protein interaction, but it's most commonly associated with the proteasomal degradation.     Cindy St. Hilaire:              So in terms of... I guess I'm thinking in terms of PCSK9, right? So those drugs are stemming from observations in humans, right? There were humans with gain and loss of function mutations, which caused either more or less of this LDLR receptor internalization. How is this RNF130 pathway different from the PCSK9 activities?   Elizabeth Tarling:             Yeah, so PCSK9 is a secreted protein, so it's made by hepatocyte and actually other cells in the body and it's secreted and it binds to the LDL particle, LDL receptor complex, and signals for its internalization and degradation in the proteasome. So this is not ubiquitination event, this is a completely different trafficking event. And so the RNF130, actually what Bethan showed, is it directly ubiquitinates the LDL receptor itself, signaling for an internalization event and then ultimately degradation of the LDR receptor through a decorative pathway, which we also define in the study.   So these are two unique mechanisms and actually some key studies that we did in the paper were to modulate RNF130 in animals that do not have PCSK9. And so in that system where in the absence of PCSK9 you have a lot of LDR receptor in the liver that's internalizing cholesterol. What happens when you overexpress RNF130? Do you still regulate at the LDL receptor? And you absolutely do. And so that again suggests that they're two distinct mechanisms and two distinct pathways.   Cindy St. Hilaire:              That was one thing I really loved about your paper is every kind of figure or section, the question that would pop up in my head, even ones that didn't pop in my head were beautifully answered with some of these really nice animal models, which is never an easy thing, right? And so one of the things that you brought up was difficulty in making one of the animal models. And so I'm wondering if you could share a little bit for that challenge. I think one thing that we always tend to hide is just science is hard and a lot of what we do doesn't work. And I really think especially for the trainees and really everyone out there, if we kind of share these things more, it's better. So what was one of the most challenging things in this study? And I guess I'm thinking about that floxed animal.   Elizabeth Tarling:             Yeah, so I'll speak a bit about that and then I'll let Bethan address because she was really the one on the ground doing a lot of the struggles. But again, we actually weren't going to include this information in the paper. And upon discussion and actually prompted by the reviewers of the paper and some of the questions that they asked us, we realized, you know what? It's actually really important to show this and show that this happens and that there are ways around it.   And so the first story is before Bethan even arrived in the lab, we had purchased embryonic stem cells that were knockout first condition already. And so this is a knockout strategy in which the exon of interest is flanked with lots of P sites so that you can create a flox animal, but also so you can create a whole body knockout just by the insertion of this knockout first cassette.   Elizabeth Tarling:             And so we got those mice actually in the first year of Bethan joining the lab. We finally got the chimeric mice and we were able to stop reading those mice. And at the same time we tried to generate our flox animals so that we could move on to do tissue-specific studies. And Bethan can talk about the pain associated with this. But over two years of breeding, we never got the right genotypes from the different crosses that you need to do to generate the flox animal.   And it was actually in discussions with Bethan where we decided we need to go back. We need to go back to those ESLs that we purchased five years ago and we need to figure out if all of the elements that the quality control step had told us were in place are actually present. And so Bethan went back and sequenced the whole locus and the cassette to figure out what pieces were present and we found that one of the essential locks P sites that's required for every single cross from the initial animal was absent and therefore we could actually never make the mouse we wanted to make.   And so that's sort of just a lesson for people going down that route and making these tools that we need in the lab to answer these questions is that despite paying extra money and getting all of the sort of QCs that you can get before you receive the ESLs, we should have gone back and done our own housekeeping and sort of a long journey told us when we went back that we didn't have what we thought we had at the beginning. And that was a real sticking point as Bethan can-   Cindy St. Hilaire:              Yeah. And so you know you're not alone. My very first postdoc that I did, I went with a mouse that they had also bought and were guaranteed that it was a knockout and it was not. And it is a painful lesson, but it is critical to... You get over it.   So Bethan, maybe you can also tell us a little bit about what are the other kind of next things you tried? You pivoted and you pivoted beautifully because all the models you used I thought were quite elegant in terms of exactly asking the question you wanted to ask in the right cells. So can you maybe explain some of the in vivo models you used for this study?   Bethan Clifford:               Sure, there are definitely a lot. So I mean I think Liz sort of encapsulated the trouble we have with the knockout really succinctly, but actually I want to just take this moment to sort of shout out to another postdoc in the Tarling lab, Kelsey Jarrett, who was really instrumental in the pivoting to a different model. So for the knockouts when we sort of established we didn't have exactly what we thought we did and then to compound that we also weren't getting the DeLiAn ratios breeding this whole body knockout.   We wanted to sort of look at a more transient knockout model. And that's where Kelsey really stepped in and sort of led the way and she generated AAV-CRISPR for us to target RNF130 specifically in the liver. And that had the added beauty of, one, not requiring breeding to get over this hurdle of the knockout being somewhat detrimental to breeding. But it also allowed us to ask the question of what RNF130 is doing specifically in the liver where the liver regulates LDL receptor and LDL cholesterol.   And so that was one of the key models that really, really helped get this paper over the finish line. But we did a whole barrage of experiments, as you've seen. We wanted to make sure... One of the key facets of the Tarling lab is whenever you do anything, no matter what you show Liz, it will always be, "Okay, you showed it to me one way, now show it to me a different way." Can you get the same result coming at it from different ways? And if you can't, why is that? What is the regulation behind that? And so that's really what the paper is doing is asking the same question in as many ways as we can accurately and appropriately probe what RNF130 does to the LDR receptor.   So we tried gain of function studies without adenovirus overexpression. We tried transient knockdown with antisense oligonucleotides, and then we did, as I said, the AAV-CRISPR knockdown with the help of Kelsey and our whole body knockout. And then we also repeated some of these studies such as the adenovirus and the ASO in specific genetic backgrounds. So in the absence of PCSK9, can we still regulate the LDL receptor? And then we also, just to really confirm this, in the absence of the LDL receptor, do we see a difference? And the answer is no, because this effect was really dependent on that LDL receptor being present. So there was a big combination.   Cindy St. Hilaire:              It was really nice, really a beautiful step-wise progression of how to solidly answer this question. But a lot of, I think, almost all you did was in mice. And so what is the genetic evidence for relevancy in humans? Can you discuss a little bit about those databases that you then went to to investigate, is this relevant in humans?   Bethan Clifford:               I think Liz might be better off answering that question.   Elizabeth Tarling:             And I think this sort of pivots on what Bethan was saying. So when we had struggles in the lab, it was a team environment and a collaboration between people in the lab that allowed us to make that leap and make those next experiments possible to then really answer that question. And to be able to include the antisense oligonucleotides required a collaboration with industry. We were very lucky to have a longstanding collaboration with Ionis, who provided the antisense oligonucleotides.   And for the human genetics side of things, that also was a collaboration with Marcus Seldin, who was a former postdoc with Jake Lusis and is now our PI at UC Irvine. And what he helped us do is dive into those summary level databases and ask from that initial study in the NHLBI care population, do we see associations of RNF130 expression in humans with LDL cholesterol with cardiovascular outcomes. And so one database which I would recommend everybody use, it's publicly available, is the StarNet database. And it's in the paper and the website is there. And that allowed us to search for RNF130.   Elizabeth Tarling:             And what it does is it asks how RNF130 expression in different tissues is associated with cardiometabolic outcomes and actual in CAD cases and controls, so people with and without heart disease. And we found that expression of RNF130 in the liver was extremely strongly correlated with the occurrence of cardiovascular disease in people with CAD. So in cases versus controls. And then we were also able to find many other polymorphisms in the RNF130 locus that were associated with LDL cholesterol in multiple different studies.   And I think the other message from this paper is this, unlike PCSK9 and unlike LDR receptor itself, which are single gene mutations that cause cardiovascular disease, there are many sub genome-wide significant loci that contribute to this multifactorial disease, which is extremely complex. And I think RNF130 falls within that bracket that those sort of just on the borderline of being genome-wide significant still play significant biological roles in regulating these processes. And they don't come up as a single gene hit for a disease, but combinatorialy they are associated with increased risk of disease and they have a molecular mechanism that's associated with the disease. And so that's what Marcus helped us do in terms of the human genetics is really understand that and get down to that level of data.   Cindy St. Hilaire:              Yeah. Yeah, it really makes you want to go back and look at those. Everyone always focuses on that really high peak and those analyses, but what are all those other ones above the noise, right? So it's really important.   Elizabeth Tarling:             I think it's really hard to do that. I think that's one where people... Again, it comes down to team science and the group of people that we brought together allowed us to ask that molecular question about how that signal was associated with the phenotype. I think by ourselves we wouldn't have been able to do it.   Cindy St. Hilaire:              Yeah. So your antisense oligonucleotide experiments, they were really nice. They showed, I think it was a four-week therapy, they showed that when you injected them expression of RNF130 went down by 90%. I think cholesterol in the animals was lowered by 50 points or so. Is this kind of a next viable option? And I guess related to that, cholesterol's extremely important for everything, right? Cell membrane integrity, our neurons, all sorts of things. Is it possible with something that is perhaps really as powerful as this to make cholesterol too low?   Elizabeth Tarling:             I think that what we know from PCSK9 gain and loss of function mutations is that you can drop your plasma cholesterol to very low levels and still be okay because there are people walking around with mutations that do that. I think RNF130 is a little different in that it's clearly regulatory in a homeostatic function in that it's ubiquitously expressed and it has this role in the liver to regulate LDL receptor availability, but there are no homozygous loss of function mutants people walking around, which tells us something else about how important it is in potentially other tissues and in other pathways. And we've only just begun to uncover what those roles might be.   So I think that as a therapy, it has great potential. We need to do a lot more studies to sort of move from rodent models into more preclinical models. But I do think that the human data tell us that it's really important in other places too. And so yeah, we need to think about how best it might work as a therapy. If it's combinatorial, if it's dosed. Those are the types of things that we need to think about.   Cindy St. Hilaire:              Yeah, it's really exciting. Do you know, are there other protein targets of RNF130? Is that related to my next question of what is next?   Elizabeth Tarling:             I mean, so I should point out, so Bethan unfortunately left the lab last year for a position at Amgen where she's working on obesity and metabolic disease. But before she left, she did two very, very cool experiments searching for new targets or additional targets of RNF130. Starting in the liver, but hopefully we'll move those into other tissues. And so she did gain of function RNF130 versus what loss of function we have of RNF130, and she did specific mass spec analysis of proteins that are ubiquitinated in those different conditions. And by overlaying those data sets, we're hoping to carve out new additional targets of RNF130. And there are some, and they're in interesting pathways, which we have yet to completely test, but definitely there are additional pathways, at least when you overexpress and reduce expression. Now, whether they turn out to be, again, bonafide in vivo, actual targets that are biologically meaningful is sort of the next step.   Cindy St. Hilaire:              Yeah. Well, I'm sure with your very rigorous approach, you are going to find out and hopefully we'll see it here in the future. Dr Elizabeth Tarling and Dr Bethan Clifford, thank you so much for joining me today. I really enjoyed this paper. It's a beautiful study. I think it's a beautiful example, especially for trainees about kind of thoroughly and rigorously going through and trying to test your hypothesis. So thanks again.   Elizabeth Tarling:             Thank you.   Bethan Clifford:               Thank you very much.   Cindy St. Hilaire:              That's it for the highlights from the March 31st and April 14th issues of Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes, and #DiscoverCircRes. Thank you to our guests, Dr Liz Tarling and Dr Bethan Clifford.   This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.   This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.  

When patients face the diagnosis of a rare disease, they face a costly, uphill battle to develop a treatment for their condition… that is, if they ever do.   Dr. Stanley Crooke is aiming to change that. As the CEO of n-Lorem Foundation, his mission is to provide personalized treatments to ultra-rare disease patients for free as long as they live, no questions asked. Thanks to his humility, coupled with the generosity of other individuals and companies, ultra-rare disease patients have a renewed hope to get the treatments others may not be able to provide.   Join Dr. Crooke as he reflects on his humble beginnings at Ionis, the approach n-Lorem takes to developing drugs for ultra-rare diseases, and what the future holds for research in this area.Show Notes  n-lorem Foundation  Charles River - Rare Disease  Vital Science S4, E01 Project ALS: Fueled by Love  2021 Rare Disease Trailblazers  BioSpace: n-Lorem Foundation Preps First Doses to Treat Ultra-Rate Disease Patients for Free  Ionis Pharmaceuticals  Nature Medicine: Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis  

On the latest BioCentury This Week podcast, BioCentury's editors assess responses to their VC survey regarding the collapse of Silicon Valley Bank in light of First Citizens' acquisition of SVB. BioCentury's editors also discuss how FDA's advisory committee meeting for tofersen from Biogen and Ionis bolsters the case for neurofilament as a surrogate endpoint in amyotrophic lateral sclerosis, and why last week's FDA draft guidance on accelerated approval could make cancer drug development harder for small biotechs. This week's podcast is sponsored by Jeito Capital.

Today we have the first installment of a new series we're calling Endpoints Shorts. In these bite-size episodes, we'll be tackling important scientific concepts for people interested in ALS research, current clinical trials, and news from around the ALS space ­– all in 15 minutes or less. Our guide throughout this series will be Dr. Nadia Sethi, ALS TDI's Director of Community Outreach and Engagement. Today, Nadia joins us to talk us through the Ionis' Pharmaceuticals Fusion Clinical Trial.Support the show: https://www.als.net/donate/See omnystudio.com/listener for privacy information.

ONCE UPON A GENE - EPISODE 175 Every Patient Matters - Discovering, Developing, and Providing Experimental ASO Treatments to Nano-Rare Patients for Free with n-Lorem Founder and CEO Stan Crooke Stan Crooke is the Founder and CEO of the n-Lorem Foundation. He's also the Founder and former CEO of Ionis Pharmaceuticals, the leader in RNA-targeted therapeutics. Under his leadership at Ionis, he pioneered development of the revolutionary antisense technology platform and created one of the largest, most advanced pipelines in the biotechnology industry. His foundation is now using this technology to discover, develop and provide personalized, experimental antisense oligonucleotide medicines to nano-rare patients for free, for life.  EPISODE HIGHLIGHTS What do you do at n-Lorem? With antisense oligonucleotides (ASOs), we design chemically modified pieces of genetic information and those pieces of genetic information allow us to target a specific RNA, which is the molecule that gets transcribed from your DNA to make the protein that makes cells work. Because we now understand that code very well, and because we have a lot of experience, we can be very rational, efficient and inexpensive compared to traditional drug development. In a nano-rare patient, a patient with a unique mutation in a single gene, we begin with this incredible advantage. We can create a genetic medicine for many of these genes and mutations and do that very rapidly and inexpensively and provide medicines for free to patients. What criteria does a family need to meet to become a n-Lorem candidate? The patient has to have a disease with a mutation that is present in no more than 30 patients in the world. By definition, our patients are truly unique and extremely rare. Patients also have to be genotypically and phenotypically characterized fully. A patient has to have a qualified research physician who can do all the work to understand what's wrong with the patient and then treat the patient with an experimental medicine after we make it.  How are some of your patients doing on the drug created for them?  The first patient that was treated with a personalized ASO that we were involved in was an 18 year old German named Anna who has a rare form of ALS. It manifests itself typically in early teens, and untreated is extremely rapidly fatal. Anna was desperately ill when the ASO treatment was started and we weren't sure if we'd even get the ASO to her before in enough time. She recovered and did remarkably well. She's now walking up multiple flights of stairs on her own with no ventilator. She has a speaking tube so her mom can hear her talk for the first time in almost three years. She's also planning to go to school. Anna even wrote a personal note to me, and for a patient with ALS to have the fine motor coordination to do that is really quite astonishing.  Where do you think we're going be in 5 to 10 years with personalized medicine? We look forward to being able to treat thousands of patients, which means we'll also be learning incredible amounts from each of these patients. We are committed to sharing what we learn and we'll have our first annual meeting of investigators, patients, and parents this year. As we learn more, then I think there will be more interest in this space, and as we create a model of quality, others can follow. I hope that as n-Lorem succeeds, we serve as a model for others to follow, and we drive policy changes that will enable more people, more technologies and more organizations to come to the aid of patients who are unserved. LINKS & RESOURCES MENTIONED https://www.mi-reporter.com/opinion/show-your-stripes-to-honor-rare-disease-day-on-feb-28/ https://www.nlorem.org/ https://www.ionispharma.com/ https://twodisableddudes.com/ https://www.ultragenyx.com/rare-entrepreneur-bootcamp/ https://open.spotify.com/episode/14RO0pNneHdpYxSqEzk1l7

Description: In 2021, a work group of international experts published an update to the 2012 iteration of this guideline. To do so they reviewed the latest evidence through a systematic literature review, with the aim of providing a useful resource for clinicians caring for individuals with glomerular disease through actionable recommendations. In this episode we speak to Dr Richard Glassock, member of the work group, to hear his insights on the key takeaways from the guideline, and what has changed in this iteration. By completing this activity you can qualify for 0.25 CME credits. To claim your credits, you must listen to the podcast and successfully pass the post-module assessment at nephrology.knowledgeintopractice.com, where you can find all past episodes of the podcast as well as other free CME resources. Reference: KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021;100(4S):S1–S276. Disclosures: Dr Richard Glassock declares the following: Stock Ownership - Reata Pharmaceuticals Speakers Bureau - Aurinia Advisory Board - Alexion, Bio-Cryst, Novartis, Otsuka, RenaSight, Travere, Vertex Consultant - Alexion, Arrowhead, Aurinia, Bio-Cryst, Calliditas, Chinook, Equillium, Horizon Pharma, Ionis, Midornid, Nephro-Sys, Omeros, River3Renal, Therini Bio, Travere, Vera Pharmaceuticals Liberum IME staff, ACHL staff and others involved with the planning, development, and review of the content for this activity have no relevant affiliations or financial relationships to disclose. The Academy for Continued Healthcare Learning (ACHL) requires that the faculty participating in an accredited continuing education activity disclose all affiliations or other financial relationships within 24 months (1) with the manufacturers of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation and (2) with any ineligible companies. All relevant financial relationships have been mitigated prior to this activity. The content for this series was developed independently of the ineligible companies. All materials are included with permission. The opinions expressed are those of the faculty and are not to be construed as those of the publisher or grantors. This educational activity was planned and produced in accordance with the ACCME Standards for Integrity and Independence in Accredited Continuing Education. Recommendations involving clinical medicine in continuing medical education (CME/CE) activity must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients. All scientific research referred to, reported, or used in CME/CE in support or justification of a patient care recommendation must conform to the generally accepted standards of experimental design, data collection, and analysis. Discussion of Off-Label, Investigational or Experimental Drug Use: Corticosteroids are mentioned in the context of the treatment of FSGS. Funding: This independent educational activity is supported by an educational grant from Travere Therapeutics. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; Travere Therapeutics has had no influence on the content of this education.

Synopsis: Stanley Crooke is Founder and CEO of n-Lorem Foundation, a nonprofit with the goal of discovering, developing and providing experimental ASO treatments to nano-rare patients for free for life. He joins us for a discussion about the business model behind rare diseases and how n-Lorem is looking to industrialize and scale the treatment of this unique population. Stanley talks about the challenges behind developing and bringing a new modality to the clinic, the company's collaboration with the FDA, and how n-Lorem seeks to be sustainable and scalable over time. Biography: Dr. Crooke is the founder, chairman and chief executive officer of n-Lorem, a nonprofit foundation focused on providing treatments for patients with nano-rare disease (1 to 30 patients worldwide), which he initiated in January 2020. Prior to n- Lorem, Dr. Crooke founded and was Chairman and Chief Executive Officer and Lead Scientist of Ionis Pharmaceuticals. During his tenure at Ionis, he led the scientific development of a new platform for drug discovery, antisense technology and the creation of one of the largest and more advanced development pipelines in the biotechnology industry, and commercialized several antisense drugs including, Spinraza, Tegsedi and others. Early in Dr. Crooke's career, he led the creation of the first broad anticancer program in the industry at Bristol-Myers, bringing numerous anticancer drugs to the market in the first five years of his career. He then assumed responsibility for worldwide R&D (president) at SmithKline Beckman (now GSK). During his tenure at SKB, Dr. Crooke led the restructuring of R&D and the development of several drugs that were commercialized. Dr. Crooke has also contemporaneously led a successful academic career becoming a full professor at Baylor College of Medicine and the University of Pennsylvania Medical School where he trained a number of PhD students and won several teaching awards. Dr. Crooke has been an active scientist throughout his career as well. Dr. Crooke has received a number of awards, most recently, Prix Galein Roy Vagellos Pro Bono Humanum Award, the American Chemical Society's E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances, the Lifetime Achievement Award presented by the Oligonucleotide Therapeutics Society, the Scrip Lifetime Achievement Award and the 2019 Massry Prize. Dr. Crooke received his M.D. and Ph.D. degrees and house staff training at Baylor College of Medicine and has been an active scientist throughout his career. In 2021, Dr. Crooke has been named Distinguished Alumnus of both Baylor College of Medicine's Graduate and Medical schools and named one of the 20 of the most influential biopharma R&D executives by Endpoints News. He has published nearly 600 scientific publications, edited more than 20 books, has numerous patents, and led the development of more than 23 drugs that have been commercialized.

When Stan Crooke, M.D., Ph.D., ran Ionis and John Maraganore, Ph.D., ran Alnylam, they were partners that turned into rivals — and not always friendly ones — as they persevered to pursue an entirely new therapeutic space; RNA-targeted drug discovery and development. Now, the pair of drug discovery titans have united once again in support of Dr. Crooke's n-Lorem Foundation—working to provide experimental personalized medicines to the rarest of rare disease patients (nano-rare) using the antisense oligonucleotide (ASO) technology he developed at Ionis. In this episode, Stan speaks with Dr. John Maraganore about John's past, their former rivalry, and the optimism shared between the two with respect to the future of n-Lorem. Do you have a question that you'd like to ask Stan Crooke? Stan will be taking questions directly from you and other podcast listeners and dedicating an entire episode towards answering your questions! To submit a question for the upcoming Q&A episode, email podcast@nlorem.org with the subject line labeled “podcast question”. If you wish to be identified, mention your name in the email. If not, we will keep your submission anonymous. We cannot wait to hear from you!

This month on Episode 38 of Discover CircRes, host Cynthia St. Hilaire highlights original research articles featured in the Jue 24th, July 8th and July 22nd issues of the journal. This episode also features an interview with the 2022 BCBS Outstanding Early Career Investigator Award finalists, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstadt.   Article highlights:   Nguyen, et al. miR-223 in Atherosclerosis.   Choi, et al. Mechanism for Piezo1-Mediated Lymphatic Sprouting   Kamtchum-Tatuene, et al.  Plasma Interleukin-6 and High-Risk Carotid Plaques   Li, et al. 3-MST Modulates BCAA Catabolism in HFrEF   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. And today I'm going to be highlighting articles from our June 24th, July 8th and July 22nd issues of Circulation Research. I'm also going to have a chat with the finalists for the 2022 BCBS Outstanding Early Career Investigator Award, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstadt.   Cindy St. Hilaire:        The first article I want to share is from our June 24th issue and is titled, miR-223 Exerts Translational Control of Proatherogenic Genes in Macrophages. The first authors are My-Anh Nguyen and Huy-Dung Hoang, and the corresponding author is Katey Rayner and they're from the University of Ottawa. A combination of cholesterol accumulation in the blood vessels and subsequent chronic inflammation that's derived from this accumulation drive the progression of atherosclerosis. Unfortunately, current standard medications tackle just one of these factors, the cholesterol. And this might explain why many patients on such drugs still have vascular plaques. In considering treatments that work on both aspects of the disease, meaning lipid accumulation and inflammation, this group investigated the micro RNA 223 or miR-223, which is a small regulatory RNA that has been shown to suppress expression of genes involved in both cholesterol uptake and inflammatory pathways in both liver and immune cells.   Cindy St. Hilaire:        The team showed that mouse macrophages deficient in miR-223, exhibited increased expression of pro-inflammatory cytokines and reduced cholesterol efflux compared with control cells. Overexpression of miR-223 had the opposite effects. Furthermore, atherosclerosis prone mice, whose hematopoietic cells lacked miR-223, had worse atherosclerosis with larger plaques and higher levels of pro-inflammatory cytokines than to control animals with normal levels of miR-223. These findings highlight miR-223's dual prompt, antiatherogenic action, which could be leveraged for future therapies.   Cindy St. Hilaire:        The second article I want to share is from our July 8th issue of Circulation Research and is titled, Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymph Expansion. The first author is Dongwon Choi and the corresponding author is Young-Kwon Hong, and they're from UCLA.   As well as being super highways for immune cells, lymph vessels are drainage channels that help maintain fluid homeostasis in the tissues. This network of branching tubes grows as fluids begin to flow in the developing embryo. This fluid flow induces calcium influx into the lymphatic endothelial cells, which in turn promotes proliferation and migration of these cells, leading to the sprouting of lymph tubules. But how do LECs, the lymphatic endothelial cells, detect fluid flow in the first place? Piezo1 is a flow and mechanosensing protein known for its role in blood vessel development and certain mutations in Piezo1 cause abnormal lymphatic growth in humans.   Cindy St. Hilaire:        This script found that Piezo1 is expressed in the embryonic mouse LECs and that the suppression of Piezo1 inhibits both flow activated calcium entry via the channel ORAI1, as well as downstream target gene activation. Overexpression of Piezo1, by contrast, induced the target genes. The team went on to show that mice lacking either Piezo1 or ORAI1 had lymphatic sprouting defects and that pharmacological activation of Piezo1 in mice enhanced lymphogenesis and prevented edema after tail surgery. Together, the results confirmed Piezo1's role in flow dependent lymphatic growth and suggest it might be a target for treating lymphedema.   Cindy St. Hilaire:        The third article I want to share is also from our July 8th issue and is titled, Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability and Progression. The first and corresponding author of this study is Joseph Kamtchum-Tatuene from University of Alberta.   Excessive plasma cholesterol and systemic inflammation are contributing factors in atherosclerosis. While traditional remedies have been aimed at lowering patient's lipid levels, drugs that tackle inflammation are now under investigation, including those that suppress Interleukin-6, which is an inflammatory cytokine implicated in the disease. Focusing on carotid artery disease, this group conducted a prospective study to determine whether IL-6 levels correlated with disease severity. 4,334 individuals were enrolled in the cardiovascular health study cohort. They had their blood drawn and ultrasounds taken at the start of the study and five years later. This group found IL-6 was robustly correlated with and predicted plaque severity independent of other cardiovascular risk factors. This study also determined that an IL-6 blood plasma level of 2.0 picograms/mls, identified individuals with the highest likelihood of plaque, vulnerability and progression. This threshold value could be used to select patients who might benefit from novel IL-6 lowering medications.   Cindy St. Hilaire:        The last article I want to share is from our July 22nd issue of Circulation Research and is titled, Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure. The first author is Zhen Li, and the corresponding author is David Lefer from Louisiana State University. Hydrogen sulfide, or H2S, is a compound that exerts mitochondrial specific actions that include the preservation of oxidative phosphorylation, mitochondrial biogenesis and ATP synthesis, as well as inhibiting cell death. 3-mercaptopyruvate sulfurtransferase, or 3-MST, is a mitochondrial H2S producing enzyme, whose functions in cardiovascular disease are not fully understood.   Cindy St. Hilaire:        This group investigated the global effects of 3-MST deficiency in the setting of pressure overload induced heart failure. They found that 3-MST was significantly reduced in the myocardium of patients with heart failure, compared with non failing controls. 3-MST knockout mice exhibited increased accumulation of branch chain amino acids in the myocardium, which was associated with reduced myocardial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance, following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism, or administration of a potent H2S donor, ameliorated the detrimental effects of 3-MST deficiency and heart failure with reduced injection fraction. These data suggest that 3-MST derived mitochondrial H2S, may play a regulatory role in branch chain amino acid catabolism, and mediate critical cardiovascular protection in heart failure.   Cindy St. Hilaire:        Today, I'm really excited to have our guests, who are the finalists for the BCVS Outstanding Early Career Investigator Awards. Welcome everyone.   Hisayuki Hashimoto:   Thank you.   Anja Karlstaedt:          Hi.   Hisayuki Hashimoto:   Hi.   Matthew DeBerge:      Hello. Thank you.   Cindy St. Hilaire:        So the finalists who are with me today are Dr Hisayuki Hashimoto from Keio University School of Medicine in Tokyo, Japan, Dr Matthew Deberge from Northwestern University in Chicago and Dr Anja Karlstaedt from Cedar Sinai Medical Center in LA. Thank you again. Congratulations. And I'm really excited to talk about your science.   Hisayuki Hashimoto:   Thank you. Yes. Thanks, first of all for this opportunity to join this really exciting group and to talk about myself and ourselves. I am Hisayuki Hashimoto, I'm from Tokyo, Japan. I actually learned my English... I went to an American school in a country called Zaire in Africa and also Paris, France because my father was a diplomat and I learned English there. After coming back to Japan, I went to medical school. During my first year of rotation, I was really interested in cardiology, so I decided to take a specialized course for cardiology. Then I got interested in basic science, so I took a PhD course, and that's what brought me to this cardiology cardiovascular research field.   Matthew DeBerge:      So I'm currently a research assistant professor at Northwestern University. I'm actually from the Chicagoland area, so I'm really excited to welcome you all to my hometown for the BCVS meeting.   Cindy St. Hilaire:        Oh, that's right. And AHA is also there too this year. So you'll see a lot of everybody.   Matthew DeBerge:      I guess I get the home field advantage, so to speak. So, I grew up here, I did my undergrad here, and then went out in the east coast, Dartmouth College in New Hampshire for my PhD training. And actually, I was a viral immunologist by training, so I did T cells. When I was looking for a postdoctoral position, I was looking for a little bit of something different and came across Dr Edward Thorpe's lab at Northwestern university, where the interest and the focus is macrophages in tissue repair after MI. So, got into the macrophages in the heart and have really enjoyed the studies here and have arisen as a research assistant professor now within the Thorpe lab. Now we're looking to transition my own independent trajectory. Kind of now looking beyond just the heart and focusing how cardiovascular disease affects other organs, including the brain. That's kind of where I'm starting to go now. Next is looking at the cardiovascular crosstalk with brain and how this influences neuroinflammation.   Anja Karlstaedt:          I am like Hisayuki, I'm also a medical doctor. I did my medical training and my PhD in Berlin at the Charité University Medicine in Berlin, which is a medical faculty from Humboldt University and Freie University. II got really interested in mathematical modeling of complex biological systems. And so I started doing my PhD around cardiac metabolism and that was a purely core and computationally based PhD. And while I was doing this, I got really hooked into metabolism. I wanted to do my own experiments to further advance the model, but also to study more in crosstalk cardiac metabolism. I joined Dr Heinrich Taegteyer lab at the University of Texas in the Texas Medical Center, and stayed there for a couple of years. And while I was discovering some of the very first interactions between leukemia cells and the heart, I decided I cannot stop. I cannot go back just after a year. I need to continue this project and need to get funding. And so after an AHA fellowship and NIHK99, I am now here at Cedars Sinai, an assistant professor in cardiology and also with a cross appointment at the cancer center and basically living the dream of doing translational research and working in cardio-oncology.   Cindy St. Hilaire:        Great. So, Dr Hashimoto, the title of your submission is, Cardiac Reprogramming Inducer ZNF281 is Indispensable for Heart Development by Interacting with Key Cardiac Transcriptional Factors. This is obviously focused on reprogramming, but why do we care about cardiac reprogramming and what exactly did you find about this inducer ZNF281?   Hisayuki Hashimoto:   Thank you for the question. So, I mean, as I said, I'm a cardiologist and I was always interested in working heart regeneration. At first, I was working with pluripotent stem cells derived cardiomyocyte, but then I changed my field during my postdoc into directly programming by making cardiomyocyte-like cells from fiberblast. But after working in that field, I kind of found that it was a very interesting field that we do artificially make a cardiomyocyte-like cell. But when I dissected the enhanced landscape, epigenetic analysis showed that there are very strong commonalities between cardiac reprogramming and heart development. So I thought that, hey, maybe we can use this as a tool to discover new networks of heart development. And the strength is that cardiac reprogramming in vitro assay hardly opens in vivo assay, so it's really time consuming. But using dark programming, we can save a lot of time and money to study the cardiac transitional networks. And we found this DNF281 from an unbiased screen, out of 1000 human open reading frames. And we found that this gene was a very strong cardiac reprogramming inducer, but there was no study reporting about any functioning heart development. We decided to study this gene in heart development, and we found out that it is an essential gene in heart development and we were kind of able to discover a new network in heart development.   Cindy St. Hilaire:        And you actually used, I think it was three different CRE drivers? Was that correct to study?   Hisayuki Hashimoto:   Ah, yes. Yeah.   Cindy St. Hilaire:        How did you pick those different drivers and what, I guess, cell population or progenitor cell population did those drivers target?   Hisayuki Hashimoto:   So I decided to use a mesodermal Cre-driver, which is a Mesp1Cre and a cardiac precursor Cre-driver, which is the Nkx2-5 Cre and the cardiomyocyte Cre, which is the Myh6-Cre. So three differentiation stages during heart development, and we found out that actually, DNF281 is an essential factor during mesodermal to cardiac precursor differentiation state. We're still trying to dig into the molecular mechanism, but at that stage, if the DNF281 is not there, we are not able to make up the heart.   Cindy St. Hilaire:        That is so interesting. Did you look at any of the strains that survived anyway? Did you look at any phenotypes that might present in adulthood? Is there anything where the various strains might have survived, but then there's a kind of longer-term disease implicating phenotype that's observed.   Hisayuki Hashimoto:   Well, thank you for the question. Actually, the mesodermal Cre-driver knocking out the DNF281 in that stage is embryonic lethal, and it does make different congenital heart disease. And they cannot survive until after embryonic day 14.5. The later stage Nkx2-5 Cre and Myh6-Cre, interestingly, they do survive after birth. And then in adult stage, I did also look into the tissues, but the heart is functioning normally. I haven't stressed them, but they develop and they're alive after one year. It looks like there's really no like phenotype at like the homeostatic status.   Cindy St. Hilaire:        Interesting. So it's kind of like, once they get over that developmental hump, they're okay.   Hisayuki Hashimoto:   Exactly. That might also give us an answer. What kind of network is important for cardiac reprogramming?   Cindy St. Hilaire:        So what are you going to do next?   Hisayuki Hashimoto:   Thank you. I'm actually trying to dig into the transitional network of what kind of cardiac transitional network the ZNF281 is interacting with, so that maybe I can find a new answer to any etiology of congenital heart disease, because even from a single gene, different mutation, different variants arise different phenotypes in congenital heart disease. Maybe if I find a new interaction with any key cardiac transitional factors, maybe I could find a new etiology of congenital heart disease phenotype.   Cindy St. Hilaire:        That would be wonderful. Well, best of luck with that. Congratulations on an excellent study. Hisayuki Hashimoto:   Thank you.   Cindy St. Hilaire:        Dr DeBerge, your study was titled, Unbiased Discovery of Allograft Inflammatory Factor-1 as a New and Critical Immuno Metabolic Regulatory Node During Cardiac Injury. Congrats on this very cool study. You were really kind of focused on macrophages in myocardial infarction. And macrophages, they're a Jeckel Hyde kind of cell, right? They're good. They're bad. They can be both, almost at the same time, sometimes it seems like. So why were you interested in macrophages particularly in myocardial infarction, and what did you discover about this allograft inflammatory factor-1, or AIF1 protein?   Matthew DeBerge:      Thank you. That's the great question. You really kind of alluded to why we're interested in macrophages in the heart after tissue repair. I mean, they really are the central mediators at both pro-inflammatory and anti-inflammatory responses after myocardial infarction. Decades of research before this have shown that inflammation has increased acutely after MI and has also increased in heart failure patients, which really has led to the development of clinical efforts to target inflammatory mediators after MI. Now, unfortunately, the results to target inflammation after MI, thus far, have been modest or disappointing, I guess, at worst, in the respect that broadly targeting macrophage function, again, hasn't achieved results. Again, because these cells have both pro and anti-inflammatory functions and targeting specific mediators has been somewhat effective, but really hasn't achieved the results we want to see.   Matthew DeBerge:      I think what we've learned is that the key, I guess, the targeting macrophage after MI, is really to target their specific function. And this led us to sort of pursue novel proteins that are mediating macrophage factor function after MI. To accomplish this, we similarly performed an unbiased screen collecting peri-infarct tissue from a patient that was undergoing heart transplantation for end stage heart failure and had suffered an MI years previously. And this led to the discovery of allograft inflammatory factor-1, or AIF1, specifically within cardiac macrophages compared to other cardiac cell clusters from our specimen. And following up with this with post-mortem specimens after acute MI to show that AIF1 was specifically increased in macrophages after MI and then subsequently then testing causality with both murine model of permanent inclusion MI, as well as in vitro studies using bone marrow drive macrophages to dig deeper mechanistically, we found that AIF1 was crucial in regulating inflammatory programing macrophages, which ultimately culminated in worse in cardiac repair after MI.   Cindy St. Hilaire:        That's really interesting. And I love how you start with the human and then figure out what the heck it's doing in the human. And one of the things you ended up doing in the mouse was knocking out this protein AIF1, specifically in macrophage cells or cells that make the macrophage lineage. But is this factor in other cells? I was reading, it can be intracellular, it can be secreted. Are there perhaps other things that are also going on outside of the macrophage?   Matthew DeBerge:      It's a great question. First, I guess in terms of specificity, within the hematopoietic compartment, previous studies, as well as publicly available databases, have shown that AIF1 is really predominantly expressed within macrophages. We were able to leverage bone marrow chimera mice to isolate this defect to the deficiency to macrophages. But you do bring up a great point that other studies have shown that AIF1 may be expressed in other radio-resistant cell populations. I mean, such as cardiomyocytes or other treatable cells within the heart. We can't completely rule out a role for AIF1 and other cell populations. I can tell you that we did do the whole body knockout complementary to our bone marrow hematopoetic deficient knockouts, and saw that deficiency of AIF1 within the whole animal, recapitulate the effects we saw within the AIF1 deficiency within hematopoietic department.   Matthew DeBerge:      It was encouraging to us that, again, the overall role of AIF1 is pro-inflammatory after MI.   Cindy St. Hilaire:        I mean, I know it's early days, but is there a hint of any translational potential of these findings or of this protein?   Matthew DeBerge:      Yeah, I think so. To answer your question, we were fortunate enough to be able to partner with Ionis that develops these anti-sensible nucleotides so that we could specifically target AIF1 after the acute phase during MI. We saw that utilizing these anti-sensible nucleotides to deplete AIF1, again, within the whole mouse, that we were able to reduce inflammation, reduce in heart size and preserve stock function. I think there really is, hopefully a therapeutic opportunity here. And again, with it being, perhaps macrophage specific is, even much more important as we think about targeting the specific function of these cells within the heart.   Cindy St. Hilaire:        Very cool stuff. Dr Karlstaedt, the title of your submission is, ATP Dependent Citrate Lyase Drives Metabolic Remodeling in the Heart During Cancer. So this I found was really interesting because you were talking about, the two major killers in the world, right? Cardiovascular disease and cancer, and you're just going to tackle both of them, which I love. So obviously this is built on a lot of prior observations about the effects of cancer on cardiac metabolic remodeling. Can you maybe just tell us a little bit about what is that link that was there and what was known before you started?   Anja Karlstaedt:          Yeah. Happy to take that question. I think it's a very important one and I'm not sure if I will have a comprehensive answer to this, because like I mentioned at the beginning, cardio-oncology is a very new field. And the reason why we are starting to be more aware of cancer patients and their specific cardiovascular problems is because the cancer field has done such a great job of developing all these new therapeutics. And we have far more options of treating patients with various different types of cancers in particular, also leukemias, but also solid tumors. And what has that led to is an understanding that patients survive the tumors, but then 10, 20 years later, are dying of cardiovascular diseases. Those are particular cardiomyopathies and congestive heart failure patients. What we are trying, or what my lab is trying to do, is understanding what is driving this remodeling. And is there a way that we can develop therapies that can basically, at the beginning of the therapy, protect the heart so that this remodeling does not happen, or it is not as severe.   Anja Karlstaedt:          Also, identifying patients that are at risk, because not every tumor is created equally and tumors are very heterogeneous, even within the same group. To get to your question, what we found is, in collaboration actually with a group at Baylor College of Medicine, Peggy Goodell's group, who is primarily working on myeloid malignancies, is that certain types of leukemias are associated with cardiomyopathies. And so when they were focusing on the understanding drivers of leukemia, they noticed that the hearts of these animals in their murine models are enlarged on and actually developing cardiomyopathies. And I joined this project just very early on during my postdoc, which was very fortunate and I feel very lucky of having met them. What my lab is now studying here at Cedars is how basically those physiological stress and mutations coming from the tumors are leading to metabolic dysregulation in the heart and then eventually disease.   Anja Karlstaedt:          And we really think that metabolism is at the center of those disease progressions and also, because it's at the center, it should be part of the solution. We can use it as a way to identify patients that are at risk, but also potentially develop new therapies. And what was really striking for us is that when we knock down ACLY that in a willdtype heart where the mouse doesn't have any tumor disease, ACLY actually is critically important for energy substrate metabolism, which seems counterintuitive, because it's far away from the mitochondria, it's not part of directly ADP provision. It's not part of the Kreb cycle. But what we found is that when we knock it out using a CRISPR-Cas9 model, it leads to cardiomyopathy and critically disrupts energy substrate metabolism. And that is not necessarily the case when the mouse has leukemia or has a colorectal cancer, which upregulated in the beginning, this enzyme expression. And so we have now developed models that show us that this could be potentially also therapeutic target to disrupt the adverse remodeling by the tumor.   Cindy St. Hilaire:        That is so interesting. So one of the things I was thinking about too is we know that, I mean, your study is showing that, the tumor itself is causing cardiac remodeling, but we also know therapies, right? Radiation, chemotherapy, probably some immune modulatory compounds. Those probably do similar, maybe not exactly similar, but they also cause, adverse cardiac remodeling. Do you have any insights as to what is same and what is different between tumor driven and therapy driven adverse remodeling?   Anja Karlstaedt:          So we do not know a lot yet. It's still an open question about all the different types of chemotherapeutics, how they are leading to cardio toxicities. But what we know, at least from the classic anti-cyclic treatments, is right now at the core, the knowledge is that this is primarily disrupting cardiac mitochondrial function. And through that again, impairing energy provision and the interaction, again, with the immune system is fairly unknown, but we know through studies from Kathryn Moore and some very interesting work by Rimson is that myocardial infarction itself can lead to an increase in risk for tumor progression. And what they have shown as independent of each other, is that the activation of the immune system in itself can lead to an acceleration of both diseases, both the cardiac remodeling, and then also the tumor disease. We don't fully understand which drivers are involved, but we do know that a lot of the cardiomyopathies on cardiotoxicities that are chemotherapeutically driven, all have also metabolic component.   Cindy St. Hilaire:        Nice. Thank you. When I prepare for these interviews, I obviously read the abstracts for the papers, but I found myself also Googling other things after I read each of your abstracts. It was a rabbit hole of science, which was really exciting.                               I now want to transition to kind of a career angle. You all are obviously quite successful, scientifically, at the bench, right? But now you are pivoting to a kind of completely opposite slash new job, right? That of, independent researcher. I would love to hear from each of you, if there was any interesting challenge that you kind of overcame that you grew from, or if there was any bit of advice that you wish you knew ahead of time or anything like that, that some of our trainee listeners and actually frankly, faculty who can pass that information onto their trainees, can benefit from.   Anja Karlstaedt:          I think the biggest challenge for me in transitioning was actually the pandemic. Because I don't know how it was for Hisa and Matt, but trying to establish a lab, but also applying for faculty position during a major global pandemic, is challenging is not quite something that I expected that would happen. And so I think saying that and looking more conceptually and philosophically at this as, you can prepare as much as you want, but then when life just kicks in and things happen, they do happen. And I think the best is to prepare as much as you can. And then simply go with the flow. Sometimes one of my mentors, Dave Nikon, mentioned that to me when I was applying for faculty positions, it's sometimes good to just go with the flow. And as a metabolism person, I absolutely agree. And there are some things that you can do as a junior investigator.   Anja Karlstaedt:          We need to have a good network. So just very important to have good mentors. I was blessed with have those mentors, Peggy Goodell's one of them, Heinrich Taegtmeyer was another. And now with this study that we are publishing, Jim Martin and Dave Nikon were incredible. Without them, this study wouldn't have been possible and I would not be here at Cedars.   Anja Karlstaedt:          You need to reach out to other people because those mentors have the experience. They have been through some of this before. Even if they have never had a major event, like COVID-19 in their life before, because none of us had before, they had other experiences and you can rely on them and they set you then up for overcoming these challenges. And the other thing I would say, is put yourself out there, go and talk to as many people as possible or set conferences, present a poster, not only talks. Don't be disappointed if you don't get a talk, posters are really great to build this network and find other people that you probably wouldn't have encountered and apply for funding. Just again, put yourself out there and try to get the funding for your research. Even if it's small foundations, it builds up over time and it is a good practice to then write those more competitive grants.     Cindy St. Hilaire:        Dr Hashimoto, would you like to go next?   Hisayuki Hashimoto:   Just my advice is that, could be like a culture of difference, but in east Asia, like in Japan, we were taught to, do not disturb people, don't interrupt people and help people. But I realized that I wasn't really good at asking for help. After I am still not like fully independent, but I do have my own group and I have to do grant writing. I still work at the bench and then have to teach grad students, doing everything myself. I just realized it's just impossible. I didn't have time. I need like 48 hours a day. Otherwise, you won't finish it. I just realized that I wasn't really good at asking for help. So my advice would be, don't hesitate to ask for help. It's not a shame. You can't do everything by just yourself. I think, even from the postdoc, even from grad school, I think, ask for help and then get used to that. And then of course, help others. And that is the way I think to probably not get overwhelmed and not stress yourself. Science should be something fun. And if you don't ask for help and if you don't help someone, I think you are losing the chance of getting some fun part from the science.   Cindy St. Hilaire:        That's great advice. I really like that, especially because I find at least, I started my lab seven years ago now. And I remember the first couple months/year, it was extremely hard to let go, right? Like I taught my new people how to do the primary cell culture we needed, but I was terrified of them doing it wrong or wasting money or making too many mistakes. But you realize, you got to learn to trust people. Like you said, you got to learn to ask for help. And sometimes that help is letting them do it. And you doing, you're being paid now to write grants and papers. That's a big brain, you're not paid to do the smaller things. That's really great advice. I like that. Thank you. Dr DeBerge, how about you?   Matthew DeBerge:      So I guess towards a bit of life advice, I think two obvious things is one, be kind, science is hard enough as it is. So I think we should try to lift each other up and not knock each other down. And along those lines as the others have alluded to as well, one of the mantras we sort of adapted on the lab, is a rising tide raises all ships, this idea that we can work together to elevate each other's science and really, again, collaborate.   Towards the career side of things I'll just touch on, because I guess one thing I'll add, there's more than one path, I guess, to achieving your goals. I've been fortunate enough to have an NIH post-doctoral fellowship and had an AHA career development award, but I'm not a K99 recipient. Oftentimes, I think this is the golden ticket to getting the faculty job, so I'm trying to, I guess, buck trend, I just submitted an RO1. So fingers crossed that leads to some opportunity.   Even beyond academia, I'm not certain how much everyone here is involved in science Twitter, it's really become a thing over the last couple years, but I think, kind of the elephant in the room is that academia, it's really hard on the trainees nowadays to have a living wage, to go through this. I mean, I'm really excited to see my, fellow finalists here are starting their own groups and stuff, but for many, that's not the reality for many, it's just not financially feasible. So I think, kind of keeping in mind that there's many, many alternative careers, whether it's industry, whether it's consulting, science writing, etcetera, going back to what Dr Hash says, find what you love and really pursue that with passion.   Cindy St. Hilaire:        I think it's something only, I don't know, five to 10% of people go into or rather stay in academia. And that means, 90 to 95% of our trainees, we need to prepare them for other opportunities, which I think is exciting, because it means it can expand our network for those of us in academia.   Anja Karlstaedt:          I think right now it's even worse because it's about 2% of old postdocs that are actually staying and becoming independent researchers, independent or tenure track or research track. And I think I second, as what Matt said, because I play cello. I do music as a hobby and people always ask me if I'm a musician. And at the beginning I felt like, no, of course not. I'm not like Yoyo Ma. I'm just playing, it's a hobby. And then I, that got me thinking. I was like, no, of course you are because there's so many different types. And what we need to understand is that scientists, like you are always a scientist. It doesn't matter if you are working at Pfizer or if you are working at a small undergrad institution and you're teaching those next generation scientists, you are still scientist and we all need those different types of scientists because otherwise, if everybody is just a soloist, you are never going to listen to symphony. You need those different people and what we need to normalize beyond having those different career paths, is also that people are staying in academia and becoming those really incredible resources for the institutions and labs, quite frankly, of being able to retain those technologies and techniques within an institution. And I think that's something to also look forward to, that even if you're not the PI necessarily, you're the one who is driving those projects. And I hope to pass this on at some point also to my trainees that they can be a scientist, even if they're not running a lab and they become an Institute director and that's also critically important.   Cindy St. Hilaire:        There's lots of ways to do science. Thank you all so much for joining me today. Either waking up at 5:00 AM or staying up past midnight, I think it is now in Japan or close to it. So Matt and I kind of made it out okay. It's like 8:00 or 9:00 AM.   Matthew DeBerge:      Thank you.   Hisayuki Hashimoto:   My apologies for this time zone difference.   Cindy St. Hilaire:        I'm very glad to make it work. Congratulations to all of you, your presentations. I forget which day of the week they are on at BCVS, but we are looking forward to the oral presentations of these and congratulations to all of you. You are amazing scientists and I know I'm really looking forward to seeing your future work so best of luck.   Matthew DeBerge:      Thank you.   Hisayuki Hashimoto:   Thank you.   Anja Karlstaedt:          Thank you so much.   Cindy St. Hilaire:        That's it for the highlights from the June 24th, July 8th and July 22nd issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle at CircRes and hashtag Discover CircRes. Thank you to our guests. The BCVS Outstanding Early Career Investigator Award Finalists, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstaedt. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire. And this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information visit ahajournals.org.  

A Roche Genentech Alzheimer's therapy failed an important clinical trial. At the press conference that followed, the scientists involved parsed over what when wrong and what should happen next. We'll discuss this conference and dive into what scientists are saying about an Alzheimer's moonshot. But that's not all. During a panel discussion at the BIO conference, a Fierce journalist witnessed a controversial take on a diversity—which led to a conversation on diversity in biotech. Lastly, we'll take a close look at the top winners in pharma, health and wellness at the Cannes Lions International Festival of Creativity. To learn more about the topics in this episode:  Will we ever land the Alzheimer's moonshot? Genentech's crenezumab partners reflect on failure Another knock back for amyloid: Roche's approach to presymptomatic Alzheimer's ends in failure BIO: 'Diversity candidates' and knowledge 'shortfalls': Women in biotech say 'I'm here to do my job' despite toxic tropes Bausch Health pulls the plug on Solta Medical IPO and 3-way company split FDA signs off on Pfizer, Moderna COVID-19 vaccines for kids 6 months and older Galapagos finally takes M&A plunge, spending $251M for 2 biotechs in CAR-T push Hot on Alnylam's heels, AstraZeneca racks up phase 3 win for Ionis-partnered rare disease drug Big Pharmas lose out at Cannes Lions as VMLY&R sweeps health categories with campaigns for Dell and Maxx Flash Winning agency behind Cannes Lions says its double health Grand Prix win shows a major shift in thinking Fierce Biotech NextGen Virtual Event The Top Line is produced by senior multimedia producer Teresa Carey with editor-in-chief Tracy Staton, managing editor Querida Anderson and senior editors Annalee Armstrong, Ben Adams, Conor Hale and Eric Sagonowsky. The sound engineer is Caleb Hodgson. The stories are by all our “Fierce” journalists. See omnystudio.com/listener for privacy information.

TELL EVERYONE - New mom chat - Kali's article and twitter      - https://www.insider.com/my-child-diagnosed-rare-genetic-condition-syngap1-2022-6       - https://twitter.com/WorthKali - Tavillas: https://syngap.fund/susan (6/22/15)   CHECK OUT THIS CONFERENCE: https://syngap.fund/treat   DRUG CO NEWS - Anglemans and Ionis! https://www.prnewswire.com/news-releases/ionis-treatment-for-angelman-syndrome-receives-orphan-drug-and-rare-pediatric-disease-designations-from-us-fda-301566169.html  - Praxis update: At the end, scroll down.    CIITIZEN - Webinar was awesome https://syngap.fund/virginie - Sign up! https://www.ciitizen.com/syngap1/   PROBABLY GENETIC IS WORKING! - Assessment:  syngap.fund/maybe - https://symptom-checker.probablygenetic.com/syngap/  - Webinar: https://syngap.fund/PG  - Sponsored testing with Mahzi! https://mahzi.com/    REMEMBER NOT TO MISS  - June 2022 https://mailchi.mp/syngapresearchfund.org/june22   - Sign up for the EF Panel: https://bit.ly/efmen      FUNDRAISERS - MDBR: Join us and secure $30k matching funds https://syngap.fund/SRFMDBR22   - MICE: Help us Make 2!  https://syngap.fund/2mice    EVENTS - June 25 in DFW - Join us for a family meeting and hear from Dr. Perry.  Link soon. - September 12-14 in San Diego - #GlobalGenes Meeting.  Link soon. - October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala  - October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap   - November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree  - December 1 in TN - Syngap Science Meeting - https://syngap.fund/treat    This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://www.syngapresearchfund.org/syngap10-podcast   Apple podcasts: https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818    Episode 64 of #Syngap10 - June 14, 2022 #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration #EpilepsyFoundation #Praxis #ProbablyGenetic #Mahzi   Copy from letter from Praxis: Monday morning, June 6th, we published an 8K filing announcing news involving multiple programs at Praxis Precision Medicines. One of these announcements pertained to the FDA's clinical hold on our recent IND filing for PRAX-222 in SCN2A, so we wanted to share further context for it. On May 25, 2022, the Company received a communication from the U.S. Food and Drug Administration (the “FDA”) providing additional information on the clinical hold placed on the Company's Investigational New Drug application (the “IND”) for the study of PRAX-222, an antisense oligonucleotide, for the treatment of patients with SCN2A gain-of-function mutations. The communication indicated that our IND could be cleared once we submit additional documentation related to the preclinical non-human primate toxicology study that supports the proposed starting dose in the clinical study. We're requesting a Type A meeting with the FDA to confirm the study design and further clarify the requirements for dose escalation beyond the starting dose. This surely will leave our SCN2A community with questions about the timing of our path forward. While the protocol and the discussions being held with the FDA remain confidential, we will do our best to maintain transparency and responsiveness throughout the process.     We continue to be fully committed to advancing PRAX-222 to clinical study. We also want to restate that this news is specific to PRAX-222, without impact on our PRAX-562 program for SCN2A, SCN8A and TSC. In Monday's press release, we reiterated our focus on driving toward proof of concept for PRAX-562. We'll provide further updates on PRAX-562 as we approach major milestones on this path. In addition, our other programs in PCDH19 and SYNGAP1 remain on-track.     Beyond epilepsy, Monday's 8K filing announced significant news pertaining to our Aria study of PRAX-114 in Major Depressive Disorder (MDD). It is with great regret that we announce the failure of the Aria Study, a study to determine the efficacy of a GABBA PAM extrasynaptic preference medicine to achieve fast-acting, lasting reduction of symptoms of MDD. After reviewing the data and our operational controls and observing failure to achieve our primary endpoint, we determined that PRAX-114 was indeed safe but not efficacious, and no further research and development of PRAX-114 is warranted. This conclusion has a negative impact on the study of PRAX-114 to treat Post-Traumatic Stress Disorder and Essential Tremor. This is a difficult decision for the Praxis team; but our commitment and capacity to researching and developing genetic insight-based treatments for people living with disorders of the CNS is in no way diminished.

Throw the doors open, build your team, tell everyone. #S10e64 TELL EVERYONE - New mom chat - Kali's article and twitter - https://www.insider.com/my-child-diagnosed-rare-genetic-condition-syngap1-2022-6 - https://twitter.com/WorthKali - Tavillas: https://syngap.fund/susan (6/22/15) CHECK OUT THIS CONFERENCE: https://syngap.fund/treat DRUG CO NEWS - Anglemans and Ionis! https://www.prnewswire.com/news-releases/ionis-treatment-for-angelman-syndrome-receives-orphan-drug-and-rare-pediatric-disease-designations-from-us-fda-301566169.html - Praxis update: At the end, scroll down. CIITIZEN - Webinar was awesome https://syngap.fund/virginie - Sign up! https://www.ciitizen.com/syngap1/ PROBABLY GENETIC IS WORKING! - Assessment: syngap.fund/maybe - https://symptom-checker.probablygenetic.com/syngap/ - Webinar: https://syngap.fund/PG - Sponsored testing with Mahzi! https://mahzi.com/ REMEMBER NOT TO MISS - June 2022 https://mailchi.mp/syngapresearchfund.org/june22 - Sign up for the EF Panel: https://bit.ly/efmen FUNDRAISERS - MDBR: Join us and secure $30k matching funds https://syngap.fund/SRFMDBR22 - MICE: Help us Make 2! https://syngap.fund/2mice EVENTS - June 25 in DFW - Join us for a family meeting and hear from Dr. Perry. Link soon. - September 12-14 in San Diego - #GlobalGenes Meeting. Link soon. - October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala - October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap - November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree - December 1 in TN - Syngap Science Meeting - https://syngap.fund/treat This is a podcast: subscribe to and rate this 10 minute #podcast #SYNGAP10 here https://www.syngapresearchfund.org/syngap10-podcast Apple podcasts: https://podcasts.apple.com/us/podcast/syngap10-weekly-10-minute-updates-on-syngap1-video/id1560389818 Episode 64 of #Syngap10 - June 14, 2022 #F78A1 #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration #EpilepsyFoundation #Praxis #ProbablyGenetic #Mahzi Copy from letter from Praxis: Monday morning, June 6th, we published an 8K filing announcing news involving multiple programs at Praxis Precision Medicines. One of these announcements pertained to the FDA's clinical hold on our recent IND filing for PRAX-222 in SCN2A, so we wanted to share further context for it. On May 25, 2022, the Company received a communication from the U.S. Food and Drug Administration (the “FDA”) providing additional information on the clinical hold placed on the Company's Investigational New Drug application (the “IND”) for the study of PRAX-222, an antisense oligonucleotide, for the treatment of patients with SCN2A gain-of-function mutations. The communication indicated that our IND could be cleared once we submit additional documentation related to the preclinical non-human primate toxicology study that supports the proposed starting dose in the clinical study. We're requesting a Type A meeting with the FDA to confirm the study design and further clarify the requirements for dose escalation beyond the starting dose. This surely will leave our SCN2A community with questions about the timing of our path forward. While the protocol and the discussions being held with the FDA remain confidential, we will do our best to maintain transparency and responsiveness throughout the process. We continue to be fully committed to advancing PRAX-222 to clinical study. We also want to restate that this news is specific to PRAX-222, without impact on our PRAX-562 program for SCN2A, SCN8A and TSC. In Monday's press release, we reiterated our focus on driving toward proof of concept for PRAX-562. We'll provide further updates on PRAX-562 as we approach m --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Stan Crooke has been in the drug development game for a long time.  He is the founder of Ionis Pharmaceuticals and now he has pioneered a method to develop and provide medicines to Ultra Rare communities of 30 patients or less.  This idea blew our minds and I think you will enjoy hearing from Stan.