Podcasts about antisense

German-headquartered Isarna Therapeutics is developing a portfolio of antisense therapies targeting an emerging therapeutic field in human biology – transforming growth factor beta (TGF-B) signaling. Precise modulation of TGF-B pathways using antisense therapy may result in safer and more effective treatment options for a broad range of indications.The company's lead compound, ISTH0036, is in clinical development in ophthalmology.On the podcast this week we chat with René Rückert, chief operating officer at Isarna Therapeutics, who explains TGF-B and antisense oligonucleotides' role in tackling disease.00:59-02:45: About Isarna Therapeutics02:45-05:05: What is transforming growth factor beta?05:05-06:16: Why is TGF a good target?06:16-09:00: What are antisense oligonucleotides?09:00-10:02: What are antisense oligonucleotides useful for treating?10:02-11:21: What advantages do antisense oligonucleotides have?11:21-13:00: How can antisense oligonucleotides be delivered?13:00-14:58: Are antisense oligonucleotides still being researched?14:58-16:31: Are there challenges with using antisense oligonucleotides?16:31-16:56: Are many companies working on antisense oligonucleotides?16:56-18:06: Are antisense oligonucleotides best used as a monotherapy or with other treatments?18:06-20:42: What is Isarna's pipeline?20:42-22:47: How does your AMD treatment work?22:47-23:50: What is the timeline for your treatment?23:50-26:34: What can patients expect?Interested in being a sponsor of an episode of our podcast? Discover how you can get involved here! Stay updated by subscribing to our newsletter

A rather muddled first episode followed by Millennium's take on the Bad Seed.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546581v1?rss=1 Authors: Rothstein, J. D., Baskerville, V., Rapuri, S., Mehlhop, E., Jafar-nejad, P., Rigo, F., Bennett, F., Mizielinska, S., Isaacs, A., Coyne, A. N. Abstract: The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538145v1?rss=1 Authors: Barker, S. J., Thayer, M. B., Kim, C., Tatarakis, D., Simon, M., Dial, R. L., Nilewski, L., Wells, R. C., Zhou, Y., Afetian, M., Chappell, A., Chew, K. S., Chow, J., Clemens, A., Discenza, C. B., Dugas, J. C., Dwyer, C., Earr, T., Ha, C., Huynh, D., Jayaraman, S., Kwan, W., Mahon, C., Pizzo, M., Roche, E., Sanders, L., Stergioulis, A., Tong, R., Tran, H., Zuchero, J., Estrada, A. A., Gadkar, K., Koth, C. M., Sanchez, P. E., Thorne, R. G., Watts, R. J., Sandmann, T., Kane, L. A., Rigo, F., Dennis, M. S., Lewcock, J. W., DeVos, S. L. Abstract: Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.21.533602v1?rss=1 Authors: Kaurani, L., Islam, M. R., Heilbronner, U., Krüger, D. M., Zhou, J., Methi, A., Strauss, J., Pradhan, R., Burkhardt, S., Pena, T., Erlebach, L., Bühler, A., Budde, M., Senner, F., Kohshour, M. O., Schulte, E. C., Schmauss, M., Reininghaus, E. Z., Juckel, G., Kronenberg-Versteeg, D., Delalle, I., Odoardi, F., Flügel, A., Schulze, T. G., Falkai, P., Sananbenesi, F., Fischer, A. Abstract: Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR 99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p mediated inflammatory response in microglia depended on Z DNA binding protein 1 (Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529798v1?rss=1 Authors: Watanabe, N., Tone, Y., Nagata, T., Masuda, S., Saito, T., Motohashi, N., Takagaki, K., Aoki, Y., Takeda, S. Abstract: Exon-skipping therapy mediated by antisense oligonucleotides (ASOs) is expected to provide a therapeutic option for Duchenne muscular dystrophy (DMD). ASOs for exon skipping reported so far target a single continuous sequence in or around the target exon. In the present study, we investigated ASOs for exon 44 skipping (applicable to approximately 6% of all DMD patients) to improve activity by using a novel ASO design incorporating two connected sequences. Phosphorodiamidate morpholino oligomers targeting two separate sequences in exon 44 were created to simultaneously target two splicing regulators in exon 44, and their exon 44 skipping was measured. NS-089/NCNP-02 showed the highest skipping activity among the oligomers. NS-089/NCNP-02 also induced exon 44 skipping and dystrophin protein expression in cells from a DMD patient to whom exon 44 skipping is applicable. We also assessed the in vivo activity of NS-089/NCNP-02 by intravenous administration to cynomolgus monkeys. NS-089/NCNP-02 induced exon 44 skipping in skeletal and cardiac muscle of cynomolgus monkeys. In conclusion, NS-089/NCNP-02, an ASO with a novel connected-sequence design, showed both in vitro and in vivo exon-skipping activity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.14.528473v1?rss=1 Authors: Mortberg, M. A., Gentile, J. E., Nadaf, N., Vanderburg, C., Simmons, S., Dubinsky, D., Slamin, A., Maldonado, S., Petersen, C. L., Jones, N., Kordasiewicz, H. B., Zhao, H. T., Vallabh, S. M., Minikel, E. V. Abstract: Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the brain and hold the promise of treating myriad brain diseases by modulating RNA. CNS tissue is not routinely biopsied in living individuals, leading to reliance on CSF biomarkers to inform on drug target engagement. Animal models can link CSF biomarkers to brain parenchyma, but our understanding of how individual cells contribute to bulk tissue signal is limited. Here we employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and macaques treated with an ASO against PRNP. Activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect disease-relevant cells in a neuronal disorder. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

ONCE UPON A GENE - EPISODE 172 From Cancer Biologist to Rare Disease Mom - Digging Into the Data to Better Understand SCN8A with Madeleine Oudin PhD - Professor of Biomedical Engineering at Tufts Madeleine Oudin is a scientist and Tiampo Family Assistant Professor at Tufts University. Her daughter Margo has two de novo mutations in the SCN8A gene, which causes epilepsy. She's navigating life as a rare, working mom and sharing her knowledge in an understandable and accessible way for other rare parents.  EPISODE HIGHLIGHTS Can you tell us about the epilepsy conference you just attended? The SCN8 community organizes the conference for clinicians, researchers and families every year at the American Epilepsy Society meeting. There were over 35 families in attendance who have children with SCN8A and it was amazing to meet everyone in real life. What advice do you have for parents who aren't sure about attending a conference? Meeting other people has made a big difference for me and I encourage others to find their people. Going to gatherings can lead to finding resources and there's value in connecting to others and learning more about a disease. Community is everything. As a scientist and now a rare parent, how do you look through the microscope differently? The impact of genetic testing surprised me in how vital it is when it comes to rare genetic diseases. When Margo had her first seizure and had genetic testing, the results helped to connect us to community. Genetic testing is vital for families to connect them to resources. What work have you done in the SCN8A community to help other families understand the disease and advance the treatment progress? Science communication is something I'm passionate about. Since becoming a rare mom, I started an Instagram account where I explain the science of the diagnosis and break it down so the information is accessible to everyone. I recently did a webinar breaking down the different treatment strategies for SCN8A.  Can you talk about Margo's acceptance to n-Lorem? We applied with our neurologist and were accepted into the foundation to develop custom Antisense oligonucleotide (ASO) treatments. In parallel, we're doing treatments in my lab on a mouse and mouse cells, testing out different ASOs to see if we can gain any additional insights. LINKS & RESOURCES MENTIONED ONCE UPON A GENE - Episode 139 - Remember Who You Are https://effieparks.com/podcast/139-remember-who-you-are Margot_thebrave on Instagram https://www.instagram.com/margot_thebrave/ SCN8A Alliance   https://scn8aalliance.org/ American Epilepsy Society https://www.ilae.org/ The n-lorem Foundation https://www.nlorem.org/ SCN8A Unraveled https://www.youtube.com/playlist?list=PL-RngxzecxdLsaJFQyerqqfGLarDe9MUt TUNE INTO THE ONCE UPON A GENE PODCAST Spotify https://open.spotify.com/show/5Htr9lt5vXGG3ac6enxLQ7 Apple Podcasts https://podcasts.apple.com/us/podcast/once-upon-a-gene/id1485249347 Stitcher https://www.stitcher.com/podcast/once-upon-a-gene Overcast https://overcast.fm/itunes1485249347/once-upon-a-gene CONNECT WITH EFFIE PARKS Website https://effieparks.com/ Twitter https://twitter.com/OnceUponAGene Instagram https://www.instagram.com/onceuponagene.podcast/?hl=en Built Ford Tough Facebook Group https://www.facebook.com/groups/1877643259173346/ Interested in advertising on Once Upon a Gene? Email advertising@bloodstreammedia.com for more information!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.29.522258v1?rss=1 Authors: Vemula, P., Schoch, K. M., Miller, T. M. Abstract: Tauopathies, including Alzheimers disease (AD), are neurodegenerative diseases characterized by the accumulation of tau protein encoded by the MAPT (Microtubule Associated Protein Tau) gene. Various strategies targeting mechanisms to reduce tau pathology have been proposed and several tau-directed therapies are being investigated in clinical trials. Our lab previously developed a novel strategy to lower tau protein levels using antisense oligonucleotides (ASOs), showing that human tau (hTau) reduction in aged PS19 tauopathy mice reversed phosphorylated tau pathology, spared neurons, and prolonged survival. Currently, the tau-lowering ASO is being evaluated in the clinical trials with successful phase 1b results. Similarly, preclinical and clinical studies have demonstrated the use of other ASOs as effective therapeutic strategies. Acquiring ASOs for research purposes may be limited by partnerships with pharmaceutical companies. However, ASOs can be obtained through commercial vendors. The current study evaluates the efficacy of mouse and human tau-targeting ASOs obtained from a commercial vendor in various mouse models. We show that mice treated with purchased ASOs distribute among various brain cell types including neurons, microglia, and astrocytes. Mice treated with tau lowering ASOs show decreased mouse or human tau mRNA and protein levels. In addition, human tau lowering ASO-treated PS19 mice showed decreased phosphorylated tau (AT8) and gliosis relative to saline-treated PS19 mice. The results obtained in PS19 mice are consistent with data obtained from our previous study using a non-commercial tau-lowering ASO. Overall, the present study demonstrates the efficacy of commercially-available tau targeting ASOs in vivo to support their broad use by researchers. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

"I want four fried chickens and a Coke". Dr. Charis Himeda joins us as we discuss some encouraging recent data from Sarepta for one of their DMD gene therapy trials and from Avidity for their myotonic dystrophy phase I/II trial and how it all potentially impacts FSHD. In addition, we revisit the potential (or lack there of) for placental or umbilical cord derived stem cell therapy for FSHD. --- Send in a voice message: https://anchor.fm/peter-l-jones/message

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.16.516816v1?rss=1 Authors: Scoles, D. R., Paul, S., Dansithong, W., Figueroa, K. P., Gandelman, M., Royzen, F., Anderson, C. J., Pulst, S. M. Abstract: Staufen1 (STAU1) is a multifunctional RNA binding protein that controls mRNA degradation and subcellular localization. STAU1 interacts with the ATXN2 protein, that is polyglutamine expanded in spinocerebellar ataxia type 2 (SCA2). We previously showed that STAU1 is elevated and aggregated in cells from SCA2 patients, cells from amyotrophic lateral sclerosis (ALS) patients, and in SCA2 and ALS mouse models. We also found that reduction of STAU1 abundance in vivo by genetic interaction improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. Here we developed antisense oligonucleotides (ASOs) lowering STAU1 expression toward developing a therapeutic that may be effective for treating SCA2 and ALS. We performed a screen of 118 20mer phosphorothioate 2-prime-O-methoxyethyl (MOE) ASO gapmers targeting across the STAU1 mRNA coding region for lowering STAU1 expression in HEK-293 cells. ASO hits lowering STAU1 by greater than 45 % were rescreened in SCA2 patient fibroblasts, and 10 of these were tested for lowering STAU1 abundance in vivo in a new BAC-STAU1 mouse model. This identified efficacious ASOs targeting human STAU1 in vivo that normalized autophagy marker proteins, including ASO-45 that also targets mouse Stau1. When delivered by intracerebroventricular (ICV) injection, ASO-45 normalized autophagy markers and abnormal mRNA abundances in cerebella of ATXN2-Q127 SCA2 mice, as well as ChAT, NeuN and cleaved caspase-3 in spinal cord of Thy1-TDP-43 transgenic mice. Targeting STAU1 may be an effective strategy for treating ALS and SCA2 as well as other disorders characterized by its overabundance. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

03 Nov 2022 - Antisense Therapeutics Limited (ASX:ANP) Chair, Dr Charmaine Gittleson, and new Chief Commercial Officer, Dr Anthony Filippis, discuss Antisense's progress, attracting new talent to the company, and what drew Dr Filippis to the role.

In this JHEP Live the faculty discuss the use of antisense oligonucleotides and siRNAs in the treatment of chronic hepatitis B infections.FacultyProf. Joerg Petersen (Moderator)Prof. Maria Buti (Faculty)Prof. Man-Fung Yuen (Faculty)All EASL Studio Podcasts are available on EASL Campus.

For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·Newsletter Sign Up·Jubilee website·PrevMed's website·PrevMed's Rumble channel·PrevMed's YouTube channel·PrevMed's Facebook page·PrevMed's Instagram·PrevMed's LinkedIn·PrevMed's Twitter ·PrevMed's Pinterest

This episode of the Patient Empowerment Program is brought to you by Argonaut Manufacturing Services! Argonaut provides contract manufacturing and sterile fill-finish services for biopharmaceutical, diagnostics and life science organizations. Argonaut's expertise in sterile fill-finish is the last step in the complex process of providing personalized experimental ASO medicines to nano-rare patients. In today's episode, Stan provides a detailed explanation of how n-Lorem discovers and develops ASO medicines for each of our nano-rare patients. n-Lorem's mission is to provide hope and potential help to nano-rare patients for free, for life; a mission that was impossible just a few years ago. Our mission is supported by over three decades of technology advancements, the expertise and knowledge of its leadership, and the overwhelming support of donors, patients and community leaders. This enables the non-profit approach that we believe is the only way to address the needs of nano-rare patients. Thanks to our partners like Argonaut, we are able to provide hope and potential help to patients today and tomorrow. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.05.506638v1?rss=1 Authors: Uzay, B., Hokelekli, F. O., Yilmaz, M., Esen, E. C., Basar, K., Bahadir-Varol, A., Ayhan, Y., Dalkara, T., Eren-Kocak, E. Abstract: Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behavior and shows antidepressant effects through Akt and ERK1/2 pathways. NUDT6 is a protein encoded from the antisense strand of the FGF2 gene and its role in the regulation of affective behavior is unclear. Here, we show that increasing NUDT6 expression in the hippocampus results in depression-like behavior in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acts by inducing inflammatory signaling, specifically by increasing S100A9 levels, activating NF-kB, and rising microglia number along with a reduction in neurogenesis. Conversely, inhibition of hippocampal NUDT6 expression by shRNA results in antidepressant effects and increases neurogenesis without altering FGF2 levels. Together these findings suggest that NUDT6 may play a role in major depression by inducing a proinflammatory state and serve as a novel therapeutic target for antidepressant development. The opposite effects of NUDT6 and FGF2 on depression-like behavior may serve as a mechanism to fine-tune affective behavior. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behavior as well as in neuropsychiatric disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

This week was ripe with a promising future! #s10e68 Remember Episode 67? https://www.youtube.com/watch?v=dVpl1UEBVXA (Like these and subscribe to our YouTube channel). Monday - Invitae Announcement https://ir.invitae.com/news-and-events/press-releases/press-release-details/2022/Invitae-Announces-Strategic-Business-Realignment-to-Accelerate-Its-Path-to-Positive-Cash-Flow-and-Realize-Full-Potential-of-Industry-Leading-Genetics-Testing-Platform/default.aspx - Sign up for Ciitizen: https://syngap.fund/ciitizen - CMO email: “While the announcement focused primarily on our operations and product portfolio, I wanted to take this opportunity to reinforce that Invitae remains unwavering in its commitment to patients. Cultivating strong relationships with Patient Advocacy Groups remains central to our business and our patient-centric philosophy. We will continue to collaborate closely with our Patient Advocacy partners and communities to educate patients and their families on the value of genetic testing in diagnosing and potentially preventing disease. Together with you, we remain steadfast in empowering and supporting patients and highlighting the many opportunities where genetic testing may be beneficial. “ Pharmacogenetics in case you are curious: https://ir.invitae.com/news-and-events/press-releases/press-release-details/2022/Invitae-Launches-Expanded-Pharmacogenomics-Panel-and-Specialized-Mental-Health-Panel/default.aspx Tuesday - Prosser Pre-Print - Mapping PTBP splicing in human brain identifies targets for therapeutic splice switching including SYNGAP1 - “We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and non-sense mediated decay. Antisense oligonucleotides that disrupt PTBP binding sites on SYNGAP1 redirect splicing and increase gene and protein expression.” - https://twitter.com/cureSYNGAP1/status/1549408144987652104?s=20&t=u5iAtpoucdyaiT06Vt77pg Wednesday - Sample collection at Stanford. - Planning for end of year, see below. Thursday - CHOP Update - https://www.helbiglab.io/ - https://www.youtube.com/watch?v=JVTnkQCtQNo Friday - Disease concept interview, Rarebase & Colombia - WCMC is looking to add to the pile of disease concept studies, which we VERY MUCH need. For the pile see Vlaskamp 2019, Jimenez-Gomez 2019, Smith-Hicks 2021, Wright 2022, Lyons-Warren 2022. - https://www.rarebase.org/ - Vicky is also building community in LatAm, there is a reunion this weekend! https://twitter.com/VickyAArteaga/status/1544994120351059969?s=20&t=6f5x8BqfRFR5UyRvFMOc_w FUNDRAISERS - MICE: Help us Make 2! https://syngap.fund/2mice - BIRTHDAYS: https://www.facebook.com/cureSYNGAP1/fundraisers EVENTS - 7 Weeks: September 12-14 in San Diego https://globalgenes.org/event/rare-patient-advocacy-summit/ - 10 Weeks: October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala - 10 Weeks: October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap - 11 Weeks: October 12-15 in OH - Child Neurology Society - 15 Weeks: November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree - 16 Weeks: November 14-15 in MA - PMC summit titled Personalized Medicine & the Patient - 18 Weeks: December 1 & 2 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 68 of #Syngap10 - July 25, 2022 #Ciitizen #CareAboutRare #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration --- Send in a voice message: https://podcasters.spotify.com/pod/show/syngap10/message

Remember Episode 67? https://www.youtube.com/watch?v=dVpl1UEBVXA (Like these and subscribe to our YouTube channel).   Monday  - Invitae Announcement https://ir.invitae.com/news-and-events/press-releases/press-release-details/2022/Invitae-Announces-Strategic-Business-Realignment-to-Accelerate-Its-Path-to-Positive-Cash-Flow-and-Realize-Full-Potential-of-Industry-Leading-Genetics-Testing-Platform/default.aspx  - Sign up for Ciitizen: https://syngap.fund/ciitizen  - CMO email: “While the announcement focused  primarily on our operations and product portfolio, I wanted to take this opportunity to reinforce that Invitae remains unwavering in its commitment to patients. Cultivating strong relationships with Patient Advocacy Groups remains central to our business and our patient-centric philosophy.   We will continue to collaborate closely with our Patient Advocacy partners and communities to educate patients and their families on the value of genetic testing in diagnosing and potentially preventing disease. Together with you, we remain steadfast in empowering and supporting patients and highlighting the many opportunities where genetic testing may be beneficial. “ Pharmacogenetics in case you are curious: https://ir.invitae.com/news-and-events/press-releases/press-release-details/2022/Invitae-Launches-Expanded-Pharmacogenomics-Panel-and-Specialized-Mental-Health-Panel/default.aspx     Tuesday  - Prosser Pre-Print - Mapping PTBP splicing in human brain identifies targets for therapeutic splice switching including SYNGAP1    - “We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and non-sense mediated decay. Antisense oligonucleotides that disrupt PTBP binding sites on SYNGAP1 redirect splicing and increase gene and protein expression.”   - https://twitter.com/cureSYNGAP1/status/1549408144987652104?s=20&t=u5iAtpoucdyaiT06Vt77pg     Wednesday  - Sample collection at Stanford. - Planning for end of year, see below.   Thursday - CHOP Update  - https://www.helbiglab.io/   - https://www.youtube.com/watch?v=JVTnkQCtQNo    Friday - Disease concept interview, Rarebase & Colombia - WCMC is looking to add to the pile of disease concept studies, which we VERY MUCH need. For the pile see Vlaskamp 2019, Jimenez-Gomez 2019, Smith-Hicks 2021, Wright 2022, Lyons-Warren 2022. - https://www.rarebase.org/   - Vicky is also building community in LatAm, there is a reunion this weekend! https://twitter.com/VickyAArteaga/status/1544994120351059969?s=20&t=6f5x8BqfRFR5UyRvFMOc_w     FUNDRAISERS - MICE: Help us Make 2!  https://syngap.fund/2mice   - BIRTHDAYS: https://www.facebook.com/cureSYNGAP1/fundraisers     EVENTS - 7 Weeks: September 12-14 in San Diego https://globalgenes.org/event/rare-patient-advocacy-summit/   - 10 Weeks: October 8 in NJ - Caren Leib Gala https://www.syngapresearchfund.org/get-involved/fundraising/caren-leib-gala  - 10 Weeks: October 8 in SC - Scramble for SYNGAP https://www.syngapresearchfund.org/get-involved/fundraising/scramble-for-syngap   - 11 Weeks: October 12-15 in OH - Child Neurology Society  - 15 Weeks: November 12 in GA - Sparks of Hope Gala https://syngap.fund/soiree  - 16 Weeks: November 14-15 in MA - PMC summit titled Personalized Medicine & the Patient - 18 Weeks: December 1 & 2 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 68 of #Syngap10 - July 25, 2022    #Ciitizen #CareAboutRare #Syngap #epilepsy #autism #intellectualdisability #id #anxiety #raredisease #epilepsyawareness #autismawareness #rarediseaseresearch #SynGAPResearchFund #CareAboutRare #PatientAdvocacy #GCchat #Neurology #GlobalCollaboration 

Dr. Robert Brown discusses the Nature Medicine article, "Suppression of Mutant C9orf72 Expression by a Potent Mixed Backbone Antisense Oligonucleotide". Show references: https://www.nature.com/articles/s41591-021-01557-6

Dr. Jeff Ratliff discusses the suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide with Drs. Jonathan Watts and Robert Brown.

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Benoît Arsenault is a research scientist focused on understanding how lifestyle and genetic factors contribute to cardiovascular disease risk. In this episode, the discussion casts a spotlight on Lp(a)—the single most important genetically-inherited trait when it comes to atherosclerotic cardiovascular disease (ASCVD) risk. Benoît explains the biology of Lp(a), how it's inherited, the importance of measuring Lp(a) levels, and the diseases most associated with high Lp(a). He dives into data on the possible treatments for lowering Lp(a) such niacin, statins, and PCSK9 inhibitors, as well as the most exciting new potential therapeutic—antisense oligonucleotides. We discuss: How Benoît came to study Lp(a)—a new marker for cardiovascular risk [3:15]; The relationship between Lp(a) and CVD risk [6:45]; What genome-wide association studies (GWAS) revealed about Lp(a) [16:00]; Clinical tests to measure Lp(a) [22:00]; The biology of Lp(a) [25:45]; How statins lower LDL-cholesterol and why this doesn't work for an Lp(a) [29:15]; The structure of LDL-p and Lp(a) and what makes Lp(a) more atherogenic than an equivalent LDL particle [34:00]; The role of Lp(a) in aortic valve disease [42:45]; How greater numbers of Lp(a) particles are associated with increased risk of disease [48:00]; The genetics and inheritance of Lp(a) and how and when to measure Lp(a) levels [52:00]; Niacin and other proposed therapies to lower Lp(a), apoB, and CVD risk [1:00:45]; Why awareness of Lp(a) among physicians remains low despite the importance of managing risk factors for ASCVD [1:14:00]; The variability of disease in patients with high Lp(a) [1:19:00]; Diseases most associated with high Lp(a) [1:26:30]; The biology of PCSK9 protein, familial hypercholesterolemia, and the case for inhibiting PCSK9 [1:35:00]; The variability in PCSK9 inhibitors' ability to lower Lp(a) and why we need more research on individuals with high levels of Lp(a) [1:50:30]; Peter's approach to managing patients with high Lp(a), and Benoît's personal approach to managing his risk [1:54:45]; Antisense oligonucleotides—a potential new therapeutic for Lp(a) [1:57:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

We discuss the different types of antisense oligonucleotide (AON/ASO) technologies and how these can be used therapeutically for FSHD. --- Send in a voice message: https://anchor.fm/peter-l-jones/message

In this issue, explore antisense oligonucleotides, including: • An overview of recent advances with hybridization-based assays to quantify antisense oligonucleotides in support of pharmacokinetic or toxicokinetic preclinical and clinical studies; • Regulatory and bioanalytical considerations for these studies; • Two case studies illustrating Altasciences' capabilities and knowledge in the field. Click here to download a PDF, readable version of Issue 12: https://www.altasciences.com/sites/default/files/2020-11/The%20Altascientist_issue12_oligonucleotides.pdf CHAPTERS: - 0:35 — Section 1: Introduction - 1:05 — Section 2: Recent Advances in Antisense Oligonucleotide Research - 3:00 — Section 3: Regulatory Considerations - 4:49 — Section 4: Bioanalytical Considerations - 10:04 — Section 5: Case Study 1 — Resolving Issues with Matrix Effect - 12:48 — Section 6: Case Study 2 — Stability of Antisense Oligonucleotide in Tissue Matrix - 14:52 — Section 7: Conclusion About Altasciences: Altasciences is an integrated drug development solution company offering pharmaceutical and biotechnology companies a proven, flexible approach to preclinical and clinical pharmacology studies, including formulation, manufacturing, and analytical services. For over 25 years, Altasciences has been partnering with sponsors to help support educated, faster, and more complete early drug development decisions. Altasciences' integrated, full-service solutions include preclinical safety testing, clinical pharmacology and proof of concept, bioanalysis, program management, medical writing, biostatistics, clinical monitoring, and data management, all customizable to specific sponsor requirements. Altasciences helps sponsors get better drugs to the people who need them, faster.

Mark Diamond has over 30 years experience in the pharmaceutical and biotechnology industry. Before joining Antisense Therapeutics Limited as MD and CEO in 2001, Mr. Diamond was employed in the US as Director, Project Planning/Business Development at Faulding Pharmaceuticals. Prior to this he held the positions of Senior Manager, Business Development and In-licensing within Faulding's European operation based in the UK and International Business Development Manager with Faulding in Australia. https://www.antisense.com.au/ Follow us on Instagram: @TheMorningSpotlight Email us at: themorningspotlight@gmail.com www.themorningspotlight.com For title insurance inquiries contact Mike at michael.ham@ctt.com Buy Mike a Coffee!

Antisense Therapeutics: A devastating disease with no cure but hope is on the horizon Listen to ASX-listed Antisense Therapeutics Managing Director Mark Diamond talk to Matt Birney on the Bulls N' Bears Report about Antisense's clever developing drug technology that is slated to tackle a medicinal market expected to be worth US$10b by 2030. See omnystudio.com/listener for privacy information.

The genomics bubble ⬩ Affinitak fails ⬩ Lynne saves the company ⬩ Hybridon pivots ⬩ New chemistries ⬩ Regulus formed ⬩ Isis as cult See acast.com/privacy for privacy and opt-out information.

Go online to PeerView.com/DYM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in neurology discusses the use of antisense oligonucleotide therapies in patients with amyotrophic lateral sclerosis (ALS). Upon completion of this accredited CE activity, participants should be better able to: Identify common genes and cellular processes implicated in ALS pathogenesis, Recognize the mechanisms of action, efficacy, and safety profiles of emerging ALS therapies including antisense oligonucleotides, Discuss how the ALS treatment paradigm may change as a result of emerging therapies, Educate patients with ALS about ongoing clinical trials evaluating novel disease-modifying therapies.

Go online to PeerView.com/DYM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in neurology discusses the use of antisense oligonucleotide therapies in patients with amyotrophic lateral sclerosis (ALS). Upon completion of this accredited CE activity, participants should be better able to: Identify common genes and cellular processes implicated in ALS pathogenesis, Recognize the mechanisms of action, efficacy, and safety profiles of emerging ALS therapies including antisense oligonucleotides, Discuss how the ALS treatment paradigm may change as a result of emerging therapies, Educate patients with ALS about ongoing clinical trials evaluating novel disease-modifying therapies.

Go online to PeerView.com/DYM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in neurology discusses the use of antisense oligonucleotide therapies in patients with amyotrophic lateral sclerosis (ALS). Upon completion of this accredited CE activity, participants should be better able to: Identify common genes and cellular processes implicated in ALS pathogenesis, Recognize the mechanisms of action, efficacy, and safety profiles of emerging ALS therapies including antisense oligonucleotides, Discuss how the ALS treatment paradigm may change as a result of emerging therapies, Educate patients with ALS about ongoing clinical trials evaluating novel disease-modifying therapies.

Go online to PeerView.com/DYM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in neurology discusses the use of antisense oligonucleotide therapies in patients with amyotrophic lateral sclerosis (ALS). Upon completion of this accredited CE activity, participants should be better able to: Identify common genes and cellular processes implicated in ALS pathogenesis, Recognize the mechanisms of action, efficacy, and safety profiles of emerging ALS therapies including antisense oligonucleotides, Discuss how the ALS treatment paradigm may change as a result of emerging therapies, Educate patients with ALS about ongoing clinical trials evaluating novel disease-modifying therapies.

Victim "Rachel" reveals how a weekend fling with "Antisense"—now known as Jason Christopher Hughes—turned into a decades-long campaign of online attacks that destroyed her other relationships. To follow the Unraveled investigations even further, stream the specials exclusively on discovery+. Go to discoveryplus.com/unraveled to start your 7-day free trial today.**discovery+ is currently only available for US subscribers. See acast.com/privacy for privacy and opt-out information.

Victim "Rachel" reveals how a weekend fling with "Antisense"—now known as Jason Christopher Hughes—turned into a decades-long campaign of online attacks that destroyed her other relationships. To follow the Unraveled investigations even further, stream the specials exclusively on discovery+. Go to discoveryplus.com/unraveled to start your 7-day free trial today.**discovery+ is currently only available for US subscribers. See acast.com/privacy for privacy and opt-out information.

Alexis and Billy talk with "Vanessa," a victim whose life has been upended by vicious online attacks for two decades. She is one of the first victims of the serial predator known as "Antisense."To follow the Unraveled investigations even further, stream the specials exclusively on discovery+. Go to discoveryplus.com/unraveled to start your 7-day free trial today.* *discovery+ is currently only available for US subscribers. See acast.com/privacy for privacy and opt-out information.

Alexis and Billy talk with "Vanessa," a victim whose life has been upended by vicious online attacks for two decades. She is one of the first victims of the serial predator known as "Antisense."To follow the Unraveled investigations even further, stream the specials exclusively on discovery+. Go to discoveryplus.com/unraveled to start your 7-day free trial today.* *discovery+ is currently only available for US subscribers. See acast.com/privacy for privacy and opt-out information.

An article about antisense oligonucleotides was recently published in the New England Journal of Medicine. While this new medication provides an 80% reduction of Lp (a) or lipoprotein(a), it appears to be not yet ready for primetime. Lp(a) is a variation of LDL, and some known ways to decrease it include statins, niacin, apheresis, and L-carnitine.For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·PrevMed's website·PrevMed's YouTube channel·PrevMed's Facebook page

In January 2020, antisense pioneer and Ionis Pharmaceuticals founder Stanley Crooke launched a nonprofit to design and deliver custom RNA-targeted therapies free of charge for individual patients with ultra-rare diseases. The organization, n-Lorem Foundation, leverages Ionis' technology platform to speed the discovery and development of custom antisense oligonucleotides. More than a year later, the work of the foundation is well underway with a number of therapies in development to treat individual patients. We spoke to Crooke, CEO of the n-Lorem Foundation, about the need the foundation is addressing, why antisense oligonucleotides are well suited to the task, and what challenges it faces in scaling the operations to address the needs of a greater number of patients.

Biotech titan Dr. Stan Crooke joins host Kira Dineen to celebrate rare disease month! Dr. Crooke was the Founder of IONIS Pharmaceuticals, with extensive experience in the pharmaceutical industry developing more than 20 marketed drugs. He has published nearly 500 scientific publications, edited more than 20 books, and has numerous patents. Dr. Stan Crooke is now the Founder and CEO of n-Lorem Foundation, a new San Diego-based organization with an incredible mission of developing individualized RNA targeted medicines for patients with ultra-rare diseases, and providing those treatments for free, for life. These patients have extremely unique mutations and are often only one of 30 people in the entire world to have the disease. After only one year as a foundation, they’ve already made great progress for the ultra rare community, having received 50 applications from patients with ultra rare genetic mutations. Out of those 50, they have greenlighted treatment plans for nearly 20 patients - greatly exceeding application and acceptance rate expectations. On This Episode We Discuss:Rare diseases vs ultra rare diseasesChallenges treating patients with ultra rare diseases and genetic mutationsStandard process and cost of drug developmentn-Lorem’s new approach to drug development for ultra rare diseases Antisense therapies (ASOs)n-Lorem’s charitable and scalable model n-Lorem’s relationship with IONIS PharmaceuticalsPeople eligible for n-Lorem’s treatmentsHow to contact n-Lorem’s for potential treatment Drugs currently in development at n-LoremInsight on the development of SPINRAZA® for spinal muscular atrophy Learn more about n-Lorem on their website. Check out the UConn Podcast Symposium, our host Kira Dineen will be on the interdisciplinary panel taking place on February 22nd at 4PM EST. You can register to attend for free here. UConn students will be provided a Zoom link to engage in a live Q&A. The panel will also be streamed publicly via Facebook and YouTube.Stay tuned for the next new episode of DNA Today on March 5th, 2021! New episodes are released on the first and third Friday of the month. In the meantime, you can binge over 140 other episodes on Apple Podcasts, Spotify, streaming on the website, or any other podcast player by searching, “DNA Today”. Brand new in 2021, episodes are now also recorded with video which you can watch on our YouTube channel. See what else we are up to on Twitter, Instagram, Facebook, YouTube and our website, DNApodcast.com. Questions/inquiries can be sent to info@DNApodcast.com.

Morgans analyst Iain Wilkie discusses the healthcare team's initiation of coverage for Antisense Therapeutics (ASX:ANP) and highlights Neuren Pharmaceuticals (ASX:NEU) as a stock with key catalysts ahead. Check out more from Morgans: Visit the Morgans website: www.morgans.com.au Check out our blog: www.morgans.com.au/Blog On Facebook: www.facebook.com/MorgansAU On Instagram: www.instagram.com/morgans.australia On Twitter: twitter.com/morgansAU

Morgans analyst Iain Wilkie discusses the healthcare team's initiation of coverage for Antisense Therapeutics (ASX:ANP) and highlights Neuren Pharmaceuticals (ASX:NEU) as a stock with key catalysts ahead.Check out more from Morgans:Visit the Morgans website: www.morgans.com.auCheck out our blog: www.morgans.com.au/BlogOn Facebook: www.facebook.com/MorgansAUOn Instagram: www.instagram.com/morgans.australiaOn Twitter: twitter.com/morgansAU

Wie Antisense-Therapien gegen Erbkrankheiten eingesetzt werden. Außerdem: Warum der Wetterbericht manchmal einfach nicht stimmt und eine neue, heiße Spur zur dunklen Materie. Das alles im neuen Spektrum-Podcast. [01:15] Begrüßung und "Antisense-Therapien" mit Spektrum-Redakteur Frank Schubert [20:10] "Subsaisonale Wettervorhersagen" mit Spektrum-Redakteur Mike Beckers [33:50] "Dunkle Materie" mit Spektrum-Redakteur Robert Gast [44:59] VerabschiedungDer Artikel zum Nachlesen: https://detektor.fm/wissen/spektrum-podcast-antisense-therapien-wetterbericht-dunkle-materie

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.12.379164v1?rss=1 Authors: Burbano, L. E., Li, M., Jancovsky, N., Jafar-Nejad, P., Richards, K., Sedo, A., Soriano, A., Rollo, B., Jia, L., Gazina, E., Piltz, S., Adikusuma, F., Thomas, P. Q., Rigo, F., Reid, C. A., Maljevic, S., Petrou, S. Abstract: Developmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo mutations in ion channels, including gain-of-function variants in KCNT1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene silencing antisense oligonucleotide (ASO) approach. The homozygous p.P924L (L/L) mouse model recapitulates the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared to mice treated with a control ASO (non-hybridizing sequence). ASO administration at neonatal age was also well-tolerated and effective in controlling seizures and extending the lifespan of treated animals. The data presented here provides a proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies. Copy rights belong to original authors. Visit the link for more info

Wie Antisense-Therapien gegen Erbkrankheiten eingesetzt werden. Außerdem: Warum der Wetterbericht manchmal einfach nicht stimmt und eine neue, heiße Spur zur dunklen Materie. Das alles im neuen Spektrum-Podcast. [01:15] Begrüßung und "Antisense-Therapien" mit Spektrum-Redakteur Frank Schubert [20:10] "Subsaisonale Wettervorhersagen" mit Spektrum-Redakteur Mike Beckers [33:50] "Dunkle Materie" mit Spektrum-Redakteur Robert Gast [44:59] VerabschiedungDer Artikel zum Nachlesen: https://detektor.fm/wissen/spektrum-podcast-antisense-therapien-wetterbericht-dunkle-materie

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.21.349191v1?rss=1 Authors: Boutros, S. J., Raber, J., Unni, V. K. Abstract: Alpha-synuclein () is a small protein involved in neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinsons disease (PD) and Dementia with Lewy bodies (DLB). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. syn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but there are remaining questions about the progressive spreading of pathology and the cognitive and behavioral effects. Here, we induced LB-like pathology in the bilateral motor cortex of WT mice and assessed behavioral and cognitive performance. As there are no long-term effective treatments for synucleinopathies, and no therapies slow or reduce the spreading of LBs, we also assessed the effects of a mouse syn-targeted antisense oligonucleotides (ASOs) on pathology and behavioral and cognitive performance starting 5 weeks after ASO treatment. At 3 months post-PFF injection (mpi), mice injected with PFFs showed cognitive impairments and mild motor impairments. At 6 mpi, PFF-injected mice showed further cognitive and motor impairments that were partially ameliorated by the ASO. ASO treatment also reduced LB-like pathology, and pathology was significantly correlated with cognitive measures. However, the particular mouse ASO used in these assays was also associated with some possible off-target effects, defined as effects not involving lowering of syn, such as a decline in body weight. These results add to what is known about the progressive nature of the PFF model of synucleinopathies. These data also support the therapeutic potential of ASOs to improve Lewy pathology and associated behavioral and cognitive phenotypes. Copy rights belong to original authors. Visit the link for more info

It began as a Facebook post for someone looking for help getting a child with a rare neurological condition whole genome sequencing. It resulted, though, in groundbreaking work by Timothy Yu, a neurologist and attending physician in the Division of Genetics and Genomics at Boston Children's Hospital to develop a custom antisense oligonucleotide therapy for the little girl, who had a rare form of the neurodegenerative condition Batten disease. The work to design and deliver an antisense therapy in under a year has excited the rare disease community for the potential of individualized therapy that address the underlying genetic mechanisms of rare diseases. We spoke to Yu about his work, the potential to industrialize the creation and delivery of individualized therapies for rare disease patients, and the challenges that need to be addressed.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.289900v1?rss=1 Authors: Li, M., Jancovski, N., Jafar-nejad, P., Burbano, L., Rollo, B., Richards, K., Drew, L., Sedo, A., pachernegg, S., Soriano, A., Jia, L., Blackburn, T., Roberts, B., Nemiroff, A., Dalby, K., Maljevic, S., Reid, C., Rigo, F., Petrou, S. Abstract: The clinical spectrum associated with SCN2A de novo mutations (DNMs) continues to expand and includes autism spectrum disorder with or without seizures, in addition to early and late seizure onset developmental and epileptic encephalopathies (DEEs). Recent biophysical studies on SCN2A variants suggest that the majority of early seizure onset DEE DNMs cause gain of function. Gain of function in SCN2A, the principal sodium channel of excitatory pyramidal neurons, would result in heightened neuronal activity and is likely to underlie the pathology seen in early seizure onset DEE patients. Supratherapeutic dosing of the non-selective sodium channel blocker phenytoin, is effective in controlling seizures in these patients but does not impact neurodevelopment, raising the idea that more profound and specific reduction in SCN2A function could significantly improve clinical outcome. To test the potential therapeutic benefit of reducing SCN2A in early seizure onset DEE we centrally administered an antisense oligonucleotide (ASO) targeting mouse Scn2a (Scn2a ASO) to a mouse model of human SCN2A early seizure onset DEE. Mice were genetically engineered to harbour the human equivalent SCN2A p.R1882Q mutation (Q/+), one of the most recurrent mutations in early seizure onset DEE. Q/+ mice presented with spontaneous seizures at postnatal day (P) 1 and did not survive beyond P30. Intracerebroventricular Scn2a ASO administration into Q/+ mice between P1-2 (that reduced Scn2a mRNA levels by 50%) significantly extended lifespan and markedly reduced spontaneous seizures occurrence. Across a range of cognitive and motor behavioural tests, Scn2a ASO treated Q/+ mice were largely indistinguishable from wildtype (+/+) mice. Further improvements in survival and behaviour were seen by adjustment of dosing regimens during development. Scn2a ASO efficacy was also evident at the cellular level. Whole cell patch clamp recording showed that Scn2a ASO administration reversed changes in neuronal excitability in layer 2/3 pyramidal neurons of Q/+ mice to levels seen in +/+ mice. Safety was assessed in +/+ mice and showed a developmental stage dependent tolerability and a favourable therapeutic index. This study suggests that a human SCN2A gapmer ASO could profoundly and safely impact early seizure onset DEE patients and heralds a new era of precision therapy in neurodevelopmental disorders. Copy rights belong to original authors. Visit the link for more info

Stanley Crooke is the founder and former CEO of Ionis Pharmaceuticals for over 30 years. He has published more than 500 scientific publications, edited more than 20 books, has numerous patents, and led the development of more than 23 drugs that have been commercialized. He is also the founder and CEO of n-Lorem foundation, a non-profit looking to create individual treatments for patients with ultra-rare diseases caused by genetic mutations by by providing patients with free care. Dr. Crooke received his M.D. and Ph.D. degrees at Baylor College of Medicine. Some Topics Covered In this Interview: - Stanley's family background - growing up with parents who didn't graduate high school -Stanley's time at Butler studying Pharmacology -Stanley's time at Baylor College of Medicine doing his MD, Ph.D. -Stanley's time at Bristol Myers, Smith Klein Beckman -Founding Ionis Pharmaceutical and what it was like being its CEO for over 30 years -Antisense oligonucleotide technology and the scientific backlash against it in the 1990s -Stanley's View on the Scientific Community Today N-Lorem Foundation: https://www.nlorem.org/ Grateful Living Website: gratefulliving4.com My Instagram: https://www.instagram.com/aroy81547/?... Spotify Podcast Link: https://open.spotify.com/show/3Hn4ttttmbWfVqAhWh4Jhi Apple Podcast Link: https://podcasts.apple.com/ca/podcast/grateful-living/id1503185956 Topics Covered

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.25.265983v1?rss=1 Authors: Sciabola, S., Xi, H., Cruz, D., Cao, Q., Lawrence, C., Zhang, T., Rotstein, S., Hughes, J. D., Caffrey, D. R., Stanton, R. V. Abstract: PFRED a software application for the design, analysis, and visualization of antisense oligonucleotides and siRNA is described. The software provides an intuitive user-interface for scientists to design a library of siRNA or antisense oligonucleotides that target a specific gene of interest. Moreover, the tool facilitates the incorporation of various design criteria that have been shown to be important for stability and potency. PFRED has been made available as an open-source project so the code can be easily modified to address the future needs of the oligonucleotide research community. A compiled version is available for downloading at https://github.com/pfred/pfred-gui/releases as a java Jar file. The source code and the links for downloading the precompiled version can be found at https://github.com/pfred . Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.17.253526v1?rss=1 Authors: Androphy, E. J. Abstract: Spinal muscular atrophy (SMA) is a motor neuron disease and the leading cause of infant mortality. SMA results from insufficient survival motor neuron protein (SMN) levels due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. However, early intervention is required for optimal outcomes, and even continuous treatment maybe insufficient to restore full motor function. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We have established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 days prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first three days of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug-drug interactions. Copy rights belong to original authors. Visit the link for more info

Commentary by Dr. Valentin Fuster

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.31.216721v1?rss=1 Authors: Rigo, F., Jafar-nejad, P., Powers, B., Soriano, A., Zhao, H., Norris, D. A., Matson, J., DeBrosse-Serra, B., Watson, J., Narayanan, P., Mazur, C., Kordasiewicz, H., Swayze, E. E., Narayanan, P. Abstract: Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing the field to develop ASOs for other neurological disorders. While SMA specifically affects spinal motor neurons, other disorders affect different central nervous system (CNS) regions, neuronal, and non-neuronal cells. Therefore, it is critically important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and robust activity throughout the CNS in neurons, oligodendrocytes, astrocytes, and microglia. This is also the case in NHP, despite larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available. Copy rights belong to original authors. Visit the link for more info

Commentary by Dr. Valentin Fuster

The cover for issue 29 of Oncotarget features Figure 5, "In vivo effects of treatment with L-Grb2 in combination with anti-angiogenic therapy in an ovarian tumor model," by Lara, et al. which reported that adaptor proteins such as growth factor receptor-bound protein-2 play important roles in cancer cell signaling. In the present study, the authors examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression in gynecologic cancer models. Murine orthotopic models of ovarian and uterine cancer were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2. Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Reverse-phase protein array analysis identified significant dysregulation of metabolites in ovarian cancer cells after Grb2 downregulation. L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. Dr. Anil K. Sood and Dr. Cristian Rodriguez-Aguayo from The University of Texas MD Anderson Cancer Center said, "Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation." Druggable targets have often been proteins with enzymatically active sites to which small molecules could bind. However, the ability to target previously undruggable targets is evolving. Small-molecule inhibitors rely on intracellular targets or antibodies to inhibit the activity of growth factors, cell surface receptors, and cytokines. The development of nucleic acid interference-based therapeutics has allowed for regulation of gene expression to inhibit elusive targets. Nucleic acid-based therapeutics involves a process in which RNA molecules or antisense oligonucleotides inhibit gene expression or translation by neutralizing targeted mRNA molecules. After crossing the cell membrane, ASOs target mRNA directly through complementary base pair interactions, in the nucleus or cytosol, thus blocking and neutralizing targeted mRNAs. The Sood/Rodriguez-Aguayo Research Team concluded in their Oncotarget Research Paper, "we report that L-Grb2 has promising antitumor activity in preclinical models of ovarian and uterine carcinoma. Whereas the evidence of L-Grb2's activity against hematological malignancies is promising, whether it is active in clinical trials against solid tumors has yet to be tested. Therapies targeting the ErbB2 receptor have had limited success in ovarian cancer, but L-Grb2 may be a better target given its status as an important converging point for cancer cell signaling pathways." Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27667 Full text - https://www.oncotarget.com/article/27667/text/ Correspondence to - Anil K. Sood - asood@mdanderson.org and Cristian Rodriguez-Aguayo - CRodriguez2@mdanderson.org Keywords - ovarian cancer, nucleic-acid based therapeutics, therapeutic approaches, uterine cancer About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.18.209270v1?rss=1 Authors: Zhang, K., Zheludev, I. N., Hagey, R. J., Wu, M. T.-P., Haslecker, R., Hou, Y. J., Kretsch, R., Pintilie, G. D., Rangan, R., Kladwang, W., Li, S., Pham, E. A., Bernardin, C., Baric, R. S., Sheahan, T. P., Dsouza, V., Glenn, J. S., Chiu, W., Das, R. Abstract: Drug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome1, 2. The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides3-6. To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve7 pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 [A], presents a topologically complex fold in which the 5' end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules. Copy rights belong to original authors. Visit the link for more info

Ionis Pharmaceuticals has been a pioneer of antisense therapies, which target RNA to either disrupt production of a disease-causing protein or upregulate needed proteins in people who are deficient. The company is in late stage development of a promising therapy to treat Huntington’s disease, a rare and fatal neurodegenerative condition. But the company is also working on advancing a new generation of antisense therapies to improve the safety and efficacy of these treatments. We spoke to Eric Swayze, senior vice president of research for Ionis, about its experimental Huntington’s disease therapy, its efforts to treat the condition, and what the next generation of antisense therapies will look like.

Morgans Senior Analyst Scott Power, spoke with Mark Diamond the CEO of Antisense Therapeutics (ANP) following the release of the positive Phase 2 Duchenne Muscular Dystrophy clinical trial results.

Morgans Research Analyst Iain Wilkie talks with Mark Diamond, Managing Director of Antisense Therapeutics (ASX:ANP). Mark shares a recap on what the company does, and what potential investors can look out for.

Morgans Research Analyst Iain Wilkie talks with Mark Diamond, Managing Director of Antisense Therapeutics (ASX:ANP). Mark shares a recap on what the company does, and what potential investors can look out for.

"Be very fair. You don't know it all. And be willing to actually listen to people. And when you're wrong, tell people you're wrong." - Nessan Bermingham: Founder, President and CEO of Triplet Therapeutics

Antisense pioneer and Ionis Pharmaceuticals Executive Chairman Stanley Crooke has launched a nonprofit to design and deliver custom RNA-targeted therapies free of charge for individual patients with ultra-rare diseases. The organization, n-Lorem Foundation, will leverage Ionis’ technology platform to speed the discovery and development of custom antisense oligonucleotide. We spoke to Crooke about the genesis of n-Lorem, how it will determine whether to work with an individual patient or researcher, and the challenges for regularizing the process of designing n-of-1 therapies for ultra-rare disease patients.

Antisense oligonucleotides (ASOs) are being developed as treatments for rare genetic disorders such as SCN2A. What are they and how do they work? To help gain a better understanding of ASOs and their role we talk to Dr Stanley Crooke, founder of Ionis. Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A. Leave a review and subscribe via Apple Podcasts.  You can also find SCN2A Insights on Spotify, and Google Podcasts or in your podcast app Links American Epilepsy Society meeting Summary of ASO presentations at AES Dr Ana Mignorance - @CNSDrugHunter on Twitter Ionis  Webinar on ASO treatment for gain of function SCN2A

How does a potential drug discovered in the lab ultimately end up in people? We tackle this question in the context of exciting gene-modifying therapies called antisense oligonucleotides (ASOs). In this episode, we speak with Dr. Tim Miller to break down the science behind ASOs and learn more about his work in finding a cure for a genetic form of amyotrophic lateral sclerosis (ALS). This episode was written and produced by Nancy Cai, Devika Nair, and Arja Ray. Music used in this episode: “Thannoid”, “Bundt”, “Lupi”, “Partly Sage”, “Beignet”, “Trailrunner”, “Game Hens”, “Lord Weasel”, “The Zeppelin”, “Dorica”, “Our Fingers Cold”, “Gaena” by Blue Dot Sessions For more information about spinal muscular atrophy (SMA), check out the spinal muscular dystrophy association website: https://www.mda.org/disease/spinal-muscular-atrophy. There is also this great animation that shows how the Spinraza (nusinersen) ASO works in the body: https://www.spinraza.com/en_us/home/taking/how-spinraza-works.html. To read the results from the first ASO for Huntington’s disease, check out the New England Journal of Medicine article here: https://www.nejm.org/doi/full/10.1056/NEJMoa1900907?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed.

2x03 'Sense and Antisense' - Episode Analysis In the latest episode, host Kurt North and guest James McLean talk Season 2 episode, 'Sense and Antisense'... Host / Editor Kurt North Guest James McLean Twitter: @thetimeisnowpod We Made This on Twitter: @wemadethispod Music by Michael Gehrmann

2x03 'Sense and Antisense' - Episode AnalysisIn the latest episode, host Kurt North and guest James McLean talk Season 2 episode, 'Sense and Antisense'...Host / EditorKurt NorthGuestJames McLeanTwitter: @thetimeisnowpodWe Made This on Twitter: @wemadethispodMusic by Michael Gehrmann

Dr. Jason Crowell discusses Richard Robinson's article on an antisense oligonucleotide therapy for a rare variant of Batten Disease. To learn more, read the article "An Antisense Oligonucleotide Therapy Looks Promising for a Rare Form of Batten Disease" by Robinson in the June 20, 2019, issue of Neurology Today—available online at http://bit.ly/NT-Batten.

A number of rare, genetic diseases including Huntington’s disease and myotonic dystrophy belong to a group of conditions known as repeat expansion disorders. Though it's normal to have pieces of repeating genetic code, these diseases involve an abnormally high number of repeats that result in the production of toxic proteins. NeuBase Therapeutics is using its platform technology to produce antisense drugs that it believes have distinct advantages over existing antisense drugs today. NeuBase recently announced a reverse merger with Ohr Pharmaceutical that propels the pre-clinical stage company onto the Nasdaq market. We spoke to Dietrich Stephan, CEO of Neubase, about repeat expansion disorders, the company’s platform technologies, and why he believes it has distinct advantages over existing therapies that target RNA.

As CEO of Ionis Pharmaceuticals, Stanley Crooke has been a pioneer in the development of antisense drugs and oversees one of the industry’s largest and most advanced pipelines. Antisense drugs are compelling for rare diseases because of their ability to selectively target specific RNA sequences. These drugs, such as the company’s treatment for spinal muscular atrophy, Spinraza, are transforming the outlook for rare disease patients. We spoke to Crooke about Ionis’ ability to succeed as a platform technology company, why he thinks gene therapy will not pose a threat to the company’s antisense platform, and why he sees the value of these therapies withstanding growing pricing pressures.

Promising results from a small clinical trial of Huntingdon's disease patients have led to RNA-directed therapy such as antisense RNA being hailed as possibly a turning point in the treatment of neurodegenerative diseases. Adam Rutherford discusses this class of drugs with Heidi Ledford of Nature News. At the beginning of the month, Donald Trump decreed that two national monument landscapes be drastically down-sized. Strict protections against exploitation were removed from vast tracts of land bearing some of the world's most important fossil bearing strata. President of the Society of Vertebrate Paleontologists, Professor David Polly explains why his organisation is now suing Trump. At Harvard University, bioengineers are growing parts of functioning kidneys in small chips using a form of 3D printing. Jennifer Lewis' lab is doing this to learn how kidneys function and explore the possible therapeutic applications of the mini-kidneys-in-a-chip. Roland Pease visits the team at work. The electric eel can deliver a 600 volt shock, from a stack of electrically charged cells along the length of its body. Inspired by the eel's biology, Michael Mayer and his colleagues at the Universities of Fribourg and Michigan have now created their own version of its electric organ with the help of jelly babies and clever origami. In the future, it could power devices in the human body.

At the ABN annual meeting 2017, David Burn interviews Kevin Talbot on the his talk on Antisense treatments in spinal muscular atrophy. The ABN Autumn Meeting took place on Wednesday 3rd May in Liverpool. For more content on this topic please visit: pn.bmj.com/

Based on the ABN's Autumn Meeting, Martin Turner interviews Matthew Wood on the his lecture Antisense treatments in neurological disease. The ABN Autumn Meeting took place on 20th October 2016 in London. For more content on this topic please visit: pn.bmj.com/

International Parkinson and Movement Disorder Society Movement Disorders Journal podcast September 2014

Clotilde Lagier-Tourenne, Assistant Investigator, Ludwig Institute for Cancer Research, Assistant Professor, Department of Neurosciences, University of California, San Diego, La Jolla - USA - speaks on "Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration - RNA Metabolism: Changing Paradigms in Neurodegeneration” This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Jeff Rothstein MD PhD, director of the Packard Center for ALS Research at Johns Hopkins University School of Medicine, talks C9ORF72 and potential treatments for this form of ALS going forward. Read more: http://blogs.als.net/post/2012/10/29/ALS-dressed-to-the-C9s.aspx

Dr. Arthur Burghes discusses antisense oligomer treatment in an SMA mouse model Guest: Arthur Burghes, PhD, professor of Molecular and Cellular Biochemistry, Molecular Genetics and Neurology, The Ohio State University

Dr. Arthur Burghes discusses antisense oligomer treatment in an SMA mouse model Guest: Arthur Burghes, PhD, professor of Molecular and Cellular Biochemistry, Molecular Genetics and Neurology, The Ohio State University

Guest: Professor Steve Wilton, Australian Neuromuscular Research Institute, The University of Western Australia Access an abstract of this month’s featured research article: Dystrophin isoform induction in vivo by antisense-mediated alternative splicing. Mol Ther. 2010 Jun;18(6):1218-23.

Guest: Professor Steve Wilton, Australian Neuromuscular Research Institute, The University of Western Australia Access an abstract of this month’s featured research article: Dystrophin isoform induction in vivo by antisense-mediated alternative splicing. Mol Ther. 2010 Jun;18(6):1218-23.

Guest: Dr. Annemieke Aartsma-Rus, DMD Genetic Therapy Group, Dept. of Human Genetics, Leiden University Medical Center, The Netherlands Access an abstract of this Month's Featured Research Article: Progress in therapeutic antisense applications for neuromuscular disorders. Eur J Hum Genet. 2010 Feb;18(2):146-53.

Guest: Dr. Annemieke Aartsma-Rus, DMD Genetic Therapy Group, Dept. of Human Genetics, Leiden University Medical Center, The Netherlands Access an abstract of this Month's Featured Research Article: Progress in therapeutic antisense applications for neuromuscular disorders. Eur J Hum Genet. 2010 Feb;18(2):146-53.

Prion diseases are a group of rare, fatal neurodegenerative diseases, also known as transmissible spongiform encephalopathies (TSEs), that affect both animals and humans and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, chronic wasting disease in deer and elk and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination. A common hallmark of TSEs is the accumulation of an abnormal isoform (PrPSc) of the host-encoded prion protein (PrPc) in the brains of affected animals and humans. PrPc is a highly conserved cell surface sialoglycoprotein that is expressed in several cell types, mainly neuronal cells, but its normal physiological function is still not known. However, PrPc is elementary for the acquisition and the replication of prion diseases. Several inhibitors of the PrPSc formation have been reported, but none of them showed great potency in an in vivo application. Thus, the identification of the 37kDa/67kDa laminin receptor (LRP/LR) as the cell surface receptor for prions opened a new direction for the development of a TSE therapy. Currently, no treatment to slow down or stop the disease process in humans with any form of CJD is established. However, several strategies have been investigated to find an anti-prion treatment including development of a vaccination therapy and screening for potent chemical compounds. In scrapie-infected neuronal cells, which represent a widely used and well characterized in vitro model for transmissible spongiform encephalopathies, the accumulation of PrPSc has been prevented by transfection of (i) antisense LRP RNA, (ii) small interfering RNAs targeting the LRP mRNA and (iii) incubation with the polyclonal anti-LRP antibody W3. Furthermore, the knock down of surface LRP/LR resulted in a reduction of the cellular PrP levels, suggesting an interference with the PrP internalization process. Thus, LRP/LR is required for the PrPSc propagation in vitro and involved in the PrPc metabolism.Due to the existence of several LR genes, a major step to investigate the role of the 37kDa/67kDa laminin receptor in scrapie pathogenesis in vivo is the generation of transgenic mice exhibiting a lower level of LRP/LR. Hemizygous transgenic mice that express LRP/LR antisense RNA under the control of the neuron-specific enolase (NSE) promoter were generated and showed a reduced LRP/LR protein level in the cerebellum and the hippocampus. Intracerebral inoculation of these transgenic mice with the scrapie agent will show, whether the accumulation of pathogenic PrPSc in the brain is delayed or prevented due to a reduced LRP/LR level. A further therapeutic anti-prion approach is given by LRP/LR deletion mutants that can be secreted to the cell culture medium and might act as decoys. Previously, it has been demonstrated that a transmembrane deletion mutant is able to prevent PrPc binding and internalization. In vitro studies using an N-terminally truncated LRP mutant, representing the extracellular domain of LRP/LR (LRP102-295::FLAG), revealed a reduced binding of (i) recombinant cellular PrP to mouse neuroblastoma cells, (ii) infectious moPrP 27-30 to BHK21 cells and (iii) interfered with the PrPSc propagation in chronically scrapie-infected mouse neuroblastoma cells. Furthermore, a cell free binding assay demonstrated the direct binding of the LRP102-295::FLAG mutant to both PrPc and PrPSc. These results together with the finding that that endogenous LRP levels remain unaffected by the expression of the mutant indicate that the secreted LRP102-295::FLAG mutant may act in a trans-dominant negative manner as a decoy by trapping PrP molecules. To investigate the therapeutic potential of the LRP102-295::FLAG decoy mutant in vivo transgenic mice were generated ectopically expressing LRP102-295::FLAG in the brain. Animals showed no phenotype and transgene expression was detected in cortical and cerebellar brain regions. An intracerebral prion inoculation of these mice will prove whether the expression of the LRP102-295::FLAG mutant can impair the PrPSc accumulation in the brain and can thus, act as a alternative therapeutic tool in prion diseases. The recent finding that experimental introduction of RNA can be used to interfere with the function of an endogenous gene (RNA interference) provided another tool for the development of gene-specific therapeutics. In order to evaluate a gene transfer therapeutic TSE strategy, human immunodeficiency virus (HIV)-derived vectors that express short hairpin RNA (shRNA) directed against the LRP mRNA were used. Following integration of LRP-shRNA-expressing lentiviral vectors into the genome of neuronal cells efficient LRP/LR downregulation was observed. In scrapie infected neuronal cells, downregulation of the LRP gene expression resulted in a diminishment of PrPSc propagation, providing a further therapeutic strategy in the development of a TSE treatment.

Widerstandsarterien spielen eine wichtige Rolle bei der Durchblutungsregulation. Bisher konnte der wichtigste endotheliale Dilatator in diesen Gefäßen, EDHF, nicht eindeutig identifiziert werden, da pharmakologische Inhibitoren unspezifische Nebenwirkungen aufwiesen. Die spezifische Inhibition von Enzymen mittels Antisensetechnik konnte in intakten Arterien nicht durchgeführt werden, da diese nur über einen kurzen Zeitraum funktionell intakt erhalten werden konnten. Im Rahmen dieser Dissertation wurde ein neues Organkulturmodell entwickelt, in dem erstmalig die endothelabhängigen EDHF- und NO-vermittelten Dilatationen über 48 h vollständig erhalten werden konnten. Zusätzlich entwickelten die kultivierten Arterien einen mit dem frisch isolierter Arterien vergleichbaren Spontantonus und zeigten eine myogene Reaktion, die sich in Kinetik und Ausmaß der Kontraktion nicht von den Kontrollarterien unterschied. Ebenso kontrahierten die chronisch perfundierten Arterien auf Stimulation mit Noradrenalin und dilatierten nach Applikation des NO-Donors SNP in vergleichbarem Ausmaß wie frisch isolierte Arterien. Um zu untersuchen, ob möglicherweise eine CytochromP450-Epoxygenase in der Signalkaskade des EDHF eine Rolle spielt, wurde zunächst die Expression von CYP2C8 in Widerstandsarterien mittels rtPCR und in-situ-Hybridisierung nachgewiesen. Da mit dem Organkulturmodell die Arterien funktionell vollständig intakt gehalten werden konnten, wurde die Wirkung von Antisense-Oligonucleotiden, die gegen CYP2C8 gerichtet waren, untersucht. Mittels konfokaler Mikroskopie konnte gezeigt werden, dass die FITC-markierten Oligonucleotide sich nur in der Intima befanden und die Transfektion des Endothels eine hohe Effizienz aufwies. Die Transfektion hatte keinen Effekt auf die NA-induzierte Kontraktion, auf die durch NS1619 (KCa-Kanalöffner)- oder die SNP- vermittelte Relaxation, was zeigt, dass die Funktion des glatten Muskels durch die Transfektion unbeeinträchtigt blieb. Die EDHF-vermittelten Dilatationen wurden durch die Transfektion mit den Antisense-Oligonucleotiden um 76% und die korrespondierenden Calciumabfälle um 58 % reduziert, während die Kontrolltransfektionen mit Scrambled- oder Senseoligonucleotiden keinen Einfluss auf die EDHF-mediierten Dilatationen hatten. Die endothelialen Calciumanstiege nach Stimulation mit ACh blieben in den Antisense-transfizierten Arterien unverändert. Das bedeutet, dass die Signaltransduktion der ACh-Rezeptoren durch die Transfektion funktionell nicht beeinträchtigt wurde. Auf diese Weise konnte mit einem spezifischen Inhibitor gezeigt werden, dass CYP2C8 eine EDHF-Synthase ist oder dessen Metabolit einen permissiven Faktor für einen anderen EDHF darstellt und ein elementarer Bestandteil der EDHF-Signalkaskade ist. Zusätzlich wurden mit diesem Organkulturmodell die Auswirkungen des kardiovaskulären Risikofaktors Hochdruck durch isolierte Erhöhung des transmuralen Drucks auf 120 und 160 mmHg (SMA120 bzw. SMA160) während einer Kulturperiode (48 h) untersucht. In den funktionellen Testungen zeigten sich nach 48 h geringere Außendurchmesserwerte in SMA120 und SMA160 im Sinne eines Remodelings. Der erhöhte Perfusionsdruck führte darüber hinaus zu einer Verstärkung der Noradrenalin-vermittelten Kontraktion. Dies ist jedoch nicht durch eine Erhöhung der Calciumsensitivität der Myofilamente zu erklären, da diese im Vergleich zur Kontrolle unverändert war, sondern durch eine Verstärkung der NA-induzierten Calciumanstiege. Neben den Veränderungen in der glatten Muskulatur zeigte sich insbesondere auch eine Beeinträchtigung der Endothel-vermittelten Relaxationen. Die NO-mediierte Dilatation wurde durch die chronische Perfusion bei 120 mmHg um 38% reduziert und bei SMA160 vollständig aufgehoben. Ebenso wurde die EDHF-vermittelte Relaxation bei SMA120 um 20 % und bei SMA160 um 47% verringert und der korrespondierende Calciumabfall um 41 % reduziert. Diese Reduktion der endothelialen Dilatationen wurde nicht durch eine Erhöhung der Elastance der Arterienwand hervorgerufen, da die dosisabhängige SNP-mediierte Relaxation unbeeinträchtigt war. Zusätzlich scheint eine strukturelle Schädigung des Endothels durch den erhöhten Druck unwahrscheinlich, da mittels Rasterelektronenmikroskopie keine Schäden an der Intima dargestellt werden konnten. Die Expression des ACh-Rezeptors scheint auch nicht in dem Maße verringert zu sein, dass sich daraus die verringerten NO- und EDHF-mediierten Relaxationen erklären ließen, da der endotheliale Calciumanstieg in SMA120 im Vergleich zu SMA45 unverändert war. Daher wird die Beeinträchtigung durch den erhöhten Druck in einem nachgeschalteten Signaltransduktionsweg vermutet. Erhöhter transmuraler Druck hat in diesem Modell innerhalb von 2 Tagen schon zu einer erheblichen Beeinträchtigung der endothelialen Funktionen und zu einer verstärkten Reaktivität des glatten Muskels in Widerstandsarterien geführt. Zwar ist eine Erhöhung des transmuralen Drucks für 48 h nicht mit einem jahrelang bestehenden Hypertonus vergleichbar, jedoch könnte man die so erhobenen Befunde als Hinweis werten, dass eine frühzeitige konsequente antihypertensive Therapie sinnvoll ist, um die druckinduzierte Verstärkung der glattmuskulären Reaktivität und die Einschränkung der Endothelfunktion zu verringern und eine daraus resultierende weitere Erhöhung des Blutdruckes zu verhindern.

Thu, 10 Apr 2003 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/964/ https://edoc.ub.uni-muenchen.de/964/1/Jox_Ralf.pdf Jox, Ralf

Encapsulation of oligonucleotides in antibody-targeted liposomes (immunoliposomes) which bind to target cells permits intracellular delivery of the oligonucleotides. This approach circumvents problems of extracellular degradation by nucleases and poor membrane permeability which free phosphodiester oligonucleotides are subject to, but leaves unresolved the inefficiency of encapsulation of oligonucleotides in liposomes. We have coupled oligonucleotides to cholesterol via a reversible disulfide bond. This modification of oligonucleotides improved their association with immunoliposomes by a factor of about 10 in comparison to unmodified oligonucleotides. The presence of cholesteryl-modified oligonucleotides incorporated in the bilayer of liposomes did not interfere with the coupling of the targeting protein to the liposome surface. Free or cholesterol coupled oligonucleotides associated with liposomes and directed against the tat gene of HIV-1 were tested for inhibition of HIV-1 proliferation in acutely infected cells. We demonstrate that the cholesteryl-modified as well as unmodified oligonucleotides acquire the target specificity of the antibody on the liposome. Their antiviral activity when delivered into cells is sequence-specific. The activity of these modified or unmodified oligonucleotides to inhibit the replication of HIV was the same on an equimolar basis (EC50 around 0.1 μM). Cholesterol coupled oligonucleotides thus offer increased liposome association without loss of antiviral activity.

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8866/1/8866.pdf Bahn, R. S.; Scriba, Peter Christian; Heufelder, A. E.

Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/8876/1/8876.pdf Scriba, Peter Christian; Janssen, O. E.; Bahn, R. S.; Heufelder, A. E.