Podcast appearances and mentions of daniel reich

Just a couple of weeks ago, 1,800 scientists, clinicians, postdoctoral fellows, and medical residents gathered in West Palm Beach, Florida, for the Americas Committee for Treatment and Research in Multiple Sclerosis annual meeting, better known as the ACTRIMS Forum. Dr. Daniel Reich is a neurologist and neuroradiologist. He is the Director of the Translational Neuroradiology Section at the NIH National Institute of Neurological Disorders and Stroke. In his clinical practice, Dr. Reich cares for people living with MS and other neurological diseases, and he leads several clinical trials focused on multiple sclerosis. At the ACTRIMS Forum, we talked with Dr. Reich about myelin repair, how improvements in imaging have impacted diagnosing and treating MS, and what he sees in MS research today that has him excited. We have a lot to talk about! Are you ready for RealTalk MS??! SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/actrims05 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com RealTalk MS on YouTube https://www.youtube.com/@RealTalkMS Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Bonus Episode Guest: Dr. Daniel Reich Privacy Policy

At least 25 venture firms have raised a total of more than $17 billion in funds this year, with Forbion unveiling the largest-ever European biopharma fund at €1.2 billion last week. On the latest BioCentury This Week podcast, BioCentury's editors discuss how Forbion deployed its prior fund and quickly raised fresh funds and what that — and other funds — say about the state of financing private biotechs in Europe and elsewhere.The editors then assess takeaways from BioCentury's conversation with NIH's Daniel Reich on data that could shape drug development's future for progressive multiple sclerosis, and neurodegeneration broadly, as well as how the first clinical data from an RNA-editing oligonucleotide therapy from Wave Life Sciences demonstrate that it's possible to change a single base in an RNA to correct a disease-causing mutation in patients.View full story: https://www.biocentury.com/article/65392400:00 - Introduction02:48 - VC Funds11:50 - New Chapter for MS23:48 - Wave's DataTo submit a question to BioCentury's editors, email the BioCentury This Week team at podcasts@biocentury.com.Reach us by sending a text

In dieser Folge berichtet dir Daniel Reich von der Firma Malermeisterbetrieb Daniel Reich von seinen Erfahrungen und Erfolgen mit Mission Mittelstand.

Welcome to Part 1 of a special two-part RealTalk MS series highlighting conversations with past recipients of the Barancik Prize for Innovation in MS Research.  The Barancik Prize is awarded at the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, a meeting better known as the ACTRIMS Forum. Several past Barancik Prize winners gathered at the 2023 ACTRIMS Forum to celebrate the 10th anniversary of the Barancik Prize, and I took that opportunity to chat with this remarkable group of MS research all-stars.  Part 1 of Barancik Prize Conversations features the 2014 and 2016 Barancik Prize winners. Dr. Philip De Jager, of Columbia University, was awarded the Barancik Prize in 2014 for applying powerful analytic approaches to better understanding how genes and the environment interact, with the goal of developing personalized treatments for MS and, ultimately, disease prevention. Dr. Daniel Reich, of the NIH Institute of Neurological Disorders and Stroke, received the Barancik Prize in 2016 for innovating approaches to imaging MS disease activity, creating new pathways to better treatments. We have a lot to talk about! Are you ready for RealTalk MS??! About the Barancik Prize Conversations  :18 Dr. Philip De Jager  2:03 Dr. Daniel Reich   19:49 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/barancik1 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Bonus Episode: Barancik Prize Conversations -- Part 1 Guests: Dr. Philip De Jager and Dr. Daniel Reich Tags: MS, MultipleSclerosis, MSResearch, MSSociety, RealTalkMS Privacy Policy

Can a virus increase your risk for developing multiple sclerosis? Join expert Dr. Neuro and guests The Pop Historian and Andrew Jensen to learn about the surprising link between multiple sclerosis and Epstein-Barr Virus, one of the viruses that cause mono. If you liked this episode, you can follow Dr. Neuro on Twitter @neurofourier or on Twitch at twitch.tv/dr_neuro. Also, be sure to check out The Pop Historian on YouTube. I will be doing a follow-up live stream with Dr. Neuro on Saturday April 8th at 7 pm Central/8 pm Eastern on the In Plain English YouTube channel! Dr. Neuro will be answering your questions about this episode live, so be sure to tune in and ask your questions in the chat! In Plain English now has a Discord server! Join here to chat with other listeners, past experts, and guests about science, suggest new episode topics, and more! Remember to follow In Plain English on Facebook , Twitter, and Instagram to keep up with the latest announcements! If you are able, please consider becoming a Patron to help support In Plain English! And check out our Where to Listen page to subscribe to our podcast on your favorite platform! Intro/Outtro music credit: Sam Brunwasser (https://soundcloud.com/visualsnowbeats) Image Credit: Ilena George and Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

This episode discusses a newly proposed initiative by the MS Clinical Trials Committee for a mechanism-driven framework to describe multiple sclerosis; with Daniel Reich from the National Institute of Mental Health, Tanja Kuhlmann from Münster University, and host Alan Thompson from the MS Journal.

Wir vertauschen links und rechts und alles bleibt gleich. Von dieser Annahme sind Pysiker*innen lange ausgegangen. Heute wissen sie es besser. In seinem Vortrag durchleuchtet Physiker Daniel Reich die Sphären einer möglichen spiegelverkehrten Welt: dem Spiegeluniversum.

Cutting-edge research is revolutionizing how multiple sclerosis is diagnosed and monitored. The central vein sign on MRI may soon be a key way of confirming if someone has multiple sclerosis versus other conditions such as migraine, vasculitis, neurosarcoidosis and blockage of small blood vessels (from age, smoking and hypertension). Early clues on MRI imaging are shared in people with evidence of MS prior to developing symptoms (called radiologically isolated syndrome or RIS). New imaging techniques in development visualize changes in progressive multiple sclerosis like slowly-expanding lesions and inflammatory cells called microglia. Dr. Daniel Reich from the NIH covers additional topics from routine MRI monitoring of the brain and spinal cord to remyelination imaging. With incredible medical advances, some people that were considered to have multiple sclerosis are now diagnosed with neuromyelitis optica (NMO) and MOG Antibody Disease (MOGAD). Dr. Sean Pittock from Mayo Clinic shares how NMO and MOGAD are different from multiple sclerosis and reviews the alternate approaches to treatment including the 3 FDA-approved treatments for NMO, Soliris (eculizumab), Uplinza (inebilizumab) and Enspyrng (satralizumab). Latest research in screening spinal fluid and blood for clues of multiple sclerosis discussed to improve diagnosis and monitoring of the disease. Barry Singer MD, Director of The MS Center for Innovations in Care, interviews: Daniel Reich MD PhD is the Chief of the Translational Neuroradiology Section of the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH). He obtained his undergraduate degree in math and physics at Yale, PhD in neuroscience at The Rockefeller University and MD degree at Cornell. Dr. Reich completed residencies in both neurology and diagnostic radiology and a neuroradiology fellowship at John Hopkins Hospital. Sean Pittock MD is a Professor of Neurology at Mayo Clinic. His is the Director of Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology and Director of Mayo's Neuroimmunology Research Laboratory. He earned his medical degree from University College Dublin, post-doctoral degree at the Royal College of Surgeons in Ireland followed by residency and fellowship at Mayo Clinic in Rochester, Minnesota. Visit www.mslivingwell.org for more information. Share your MS story on https://ICanWithMS.org

In this episode of our Classics series, we revisit Michael Cline’s 2007 solo show “Folks” at Daniel Reich Gallery in ...

Dr. Gibbs welcomes Dr. Daniel Reich, chief of NINDS Translational Neuroradiology Section, who discusses their work using non- and minimally invasive imaging methods to study the pathobiology of multiple sclerosis. (21:56)

The pogrom of November 9, 10 of 1938: at least 91 Jews were killed, 30,000 were arrested and incarcerated in Nazi concentration camps, hundreds of synagogues were burned, and over 7,000 Jewish businesses destroyed or damaged. Can this happen again? Daniel Reich from the St. Louis Holocaust Museum & Learning Center provides insight and describes the role of the Holocaust Museum & Learning Center in educating and empowering visitors to make the world a more tolerant place by rejecting all forms of hate, racism, and bigotry. https://hmlc.org/

[intro music]   Hello, and welcome to Episode Thirty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Daniel Reich, an expert in MS neuroradiology. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Every week somewhere between 30 and 100 scientific papers related to MS are published in the peer-reviewed literature. And every Friday MSDF lists them all. You can find this week’s list, as well as three years’ worth of past lists by clicking on the Papers tab at the top of every MSDF page. In addition to listing the new papers, we also have a section containing classic papers in the field, along with commentary about what makes them classic. We’d love it if you’d like to suggest a classic paper we haven’t yet listed, and we’d love it even more if you’d like to contribute commentary. Please send your suggestions to editor at msdiscovery.org.   In addition to detailed original reports on new research, MSDF also curates MS-related news from around the Internet in a series of news briefs we call Research Roundups. In our latest Research Roundup, we reported on a second case of progressive multifocal leukoencephalopathy in a patient taking fingolimod. We mentioned a new trial of mesenchymal stem cells that will soon begin recruiting people in Canada with relapsing or progressive MS. And we pointed out that while scientific research was a favorite choice of America’s 50 biggest philanthropists last year, no neurological disease benefitted directly from the $1.6 billion they contributed. If you happen to have one of those folks on speed dial, we hope you’ll put in a good word for MS research. You can find our Research Roundups by clicking on News and Future Directions and then on News Briefs.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation, even if you’re not a billionaire. MSDF is run by a small team of reporters and editors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussions and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.   [transition music]   Now to the interview. Dr. Daniel Reich directs the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. In his practice as a neuroradiologist, he cares for patients with multiple sclerosis and other neurological diseases, and he also leads several clinical studies. Research in Dr. Reich’s lab focuses on the use of advanced MRI techniques to understand the sources of disability in multiple sclerosis and on ways of adapting those techniques for use in research trials and patient care. Dr. Reich is also a member of MSDF’s scientific advisory board. Science Journalist Carol Morton caught up with Dr. Reich at the recent Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico.   Interviewer – Carol Morton Can you tell us the value of MRI in multiple sclerosis?   Interviewee – Daniel Reich The way I see it, MRI has tremendous value in multiple sclerosis in three major ways. One is in the clinic, one is in clinical trials, and the third is really for understanding the biology of the disease; it’s an incredibly powerful tool for that. And in my own evolution as a clinician and researcher in multiple sclerosis, I’ve really moved my thinking a lot from kind of using MRI diagnostically or thinking about how we might develop markers of the disease to look at in clinical trials to really the third part, which is trying to understand the disease using the MRI, or sometimes as I call it, the MRIcroscope.   Because really it is, in a way, a scientific tool to look at aspects of the disease that we can’t access either because we can’t study the brain tissue or the spinal cord tissue directly, and because it’s really much more sensitive than doing clinical evaluations in neurology. So one of the interesting things that came out from early MRI studies in the 1990s, many of them done at the NIH long before I got there where they started doing MRIs every month on people even before the era of disease-modifying therapy, was that new plaques that appeared in the brain occurred roughly ten times more frequently than new symptoms appeared in the form of relapses.   MSDF Ten times?   Dr. Reich Ten times, or maybe even more. But that was with the sensitivity of the techniques that were available then, that was the number that was found. What that’s telling you, of course, is that there’s a lot of subclinical disease activity that’s going on that we can completely miss if we are just doing examinations or asking patients to report their symptoms.   MSDF Have there been eras of MRI use in MS and where are we now with it? And that could be in clinical trials and biology.   Dr. Reich We’ve made a lot of progress, I think, in all three areas. The MRI is absolutely the most important paraclinical tool for making the diagnosis of MS. And since the newest generation of diagnostic criteria were established, the McDonald Criteria, MRI has really formed the centerpiece of those. So in somebody who is having symptoms that may be due to multiple sclerosis, the MRI is absolutely the most important test that can be done. And, in fact, it’s now evolved to the point where the diagnosis can be made based on a single MRI at one time in many cases in somebody who comes in with the appropriate clinical symptoms.   MSDF A new challenge confronts the whole MS community in developing therapies and monitoring outcomes of interventions for progressive MS.   Dr. Reich Yes. So how might MRI play a role in assessing therapies for progressive MS? That is a huge challenge. It’s a challenge I would say the majority of my colleagues in the imaging field in MS are working on; what can you measure with MRI that might be the equivalent of new plaque development for the progressive MS question? And it’s, in my view, quite unresolved. The most studied markers that have behind them the weight of evidence to date is brain volume changes – how much brain is there – which can be assessed with MRI and is being done routinely in clinical trials now. I think how exactly that’s being done, which parts of the brain to look at – grey matter, white matter, specific portions of the brain like the thalamus – remains an open question.   What quantitative analysis tools should you use to make the measurements from the images? How you set up the scanner? All of this is still being worked out. That idea of measuring brain volume and seeing whether therapies may slow the rate of brain volume loss appears to be relatively promising. But even with that, proof of concept early trials to see whether a therapy might work are still much larger and much longer than the proof of concept trials that work for assessing new therapies to reduce the number of plaques.   MSDF By how much longer?   Dr. Reich They usually are two years or so at the minimum and they would involve on the order of 100 to 150 patients. Contrast that to four to six months with 10 to 15 patients and you can see how many more therapies can be tested with the shorter, smaller approach. So, in fact, in our lab, one of the things we’ve been thinking about a lot is how we may shorten that. And in the context of progressive multiple sclerosis, I think that’s not clear how to do. However, a lot of the biological processes that are occurring in progressive multiple sclerosis, there’s now a lot of evidence that they also occur very early in the disease, perhaps even before somebody has their first symptoms. So these brain atrophy processes, I think that’s been quite well established.   But you can also ask the question of whether brain tissue repair. Parts of the brain that have been demyelinated that requires remyelination that occurs early in the disease and it may be relevant for progressive phases of the disease as well, or for people who have primary progressive MS. And so we’ve been thinking a lot about how to look at these early plaques that develop early in the disease and use imaging of those plaques to see how they repair in order to test new therapies coming down the block that may promote remyelination or protect brain tissue that’s undergoing inflammation and demyelination from more extensive destruction. And we think, based on the some of the work we’ve done that is going to be published next week, that we can design trials that are, again, very short – six months or so with 10 to 20 patients, 15 to 20 patients – that may be able to assess that. And, of course, we’ll need to understand whether success in such a trial would predict whether that therapy would work in larger trials of progressive MS.   MSDF Are there other challenges with MRI and related to multiple sclerosis?   Dr. Reich Sure. From the point of view of doing clinical trials that are generalizable to large groups of patients that are able to be implemented at multiple sites, we need to understand how to standardize our techniques better. I’ve been involved with an effort recently to develop a group of cooperating investigators in North America similar to our older, more venerable brothers and sisters in Europe who have been working together on imaging for 20 years or so in the MAGNIMS Consortium. Our group which is called the North American Imaging in Multiple Sclerosis Cooperative – or NAIMS – is really very interested in trying to understand how we can standardize high-end approaches that may be very effective for testing new therapies that may be useful for assessing tissue or repair. With this consortium, the NAIMS Consortium, we’ve been very interested in developing standardized protocols that could be useful for assessing in a multicenter way, whether new therapies that are designed to repair or protect brain tissue and spinal cord tissue work. So we’ve been working very hard to do that, and we hope that once a study can be done in multiple sites, it can often be done much more efficiently.   From a diagnostic point of view, the types of MRIs that are done at all different centers may be equally good for just assessing, for example, whether plaques are present in the brain of somebody who is being worked-up for multiple sclerosis. But if you have to take the next step to quantify that and to submit those results to statistical analysis, then you really need a lot more homogeneity. It’s not actually clear how much homogeneity you need, how much narratization you need, that’s an open question. Does it need to be exactly the same, or does it need to be approximately the same, or really do we need to understand the differences between what is done at one site versus what is done at the other?   The last area in which I think MRI is incredibly valuable and offers something that no other technique really can is the ability to study the spatiotemporal dynamics of the disease. MS is, of course, a disease that affects people young and that they carry with them for their entire life, so it can last 40, 50, 60, 70 years in some cases. And I think we all know that the disease changes a lot during that period, and it changes as people are changing and as they age, and you can’t take pieces of the brain or spinal cord and study it under the microscope. I mentioned already that clinical evaluation is less sensitive than the MRI for picking up these changes, so only with the MRI can you understand how things change and where they’re changing in the brain.   In that context, I think people have been going along one of two pathways for how to use MRI to understand the biology of the disease. On the one hand, people have been using the physics of MRI to build really complicated models of how different types of tissue changes – demyelination, inflammation, atrophy – could affect the pictures we take, and that’s been a very interesting but quite complicated effort and the results have been a little bit hard to interpret. The other approach is to take advantage of the rapidly evolving technical changes in MRI acquisitions to really just learn how to take higher and higher resolution pictures.   And I think that’s the bias that we have in our group, that’s the approach we’re taking where we think that as we begin to hone in on really fine features of structures of the brain, whether it be the cerebral cortex or the spinal cord or the brain stem or the cerebellum, we’ll begin to see things that will help to bridge this divide between what people can do in the lab with really fancy molecular techniques with what they can do in the clinical with MRI. And so that’s really where we’ve been spending a lot of our effort using very powerful MRI machines – 7 Tesla – using very advanced antennas – we call them coils – in MRI to really get high-sensitivity images.   Changing the way we tune the magnet to focus on things that we think are interesting. For example, one of the areas we’ve been studying quite intensively recently is inflammation in the meninges in the coverings of the brain, which we think from the pathological data are quite relevant to the disease. We have a way now that we’ve described of assessing at least some of that inflammation in MS, and we’ve been following up on that. So I think the potential of MRI as a biological tool, even after 30 years of work on it, is really largely untapped.   MSDF Are there things that the MRI can’t do right now that you really want it to do?   Dr. Reich Oh, absolutely. You know, MRI is based on the physics of how protons behave in a strong magnetic field and when those protons which are largely in water are aligned when they go into a magnetic field. And we can perturb that alignment, and then it relaxes back into the equilibrium state. And the rates at which that happen depend on where these protons are located, and that’s what allows us to see the tissue. And I go into that because it just illustrates that we’re not looking at T cells and B cells and microglia and axons and oligodendrocytes, we’re looking at the physics of protons in a magnetic field.   I would, of course, love to have a technique that combines the exquisite submillimeter spatial resolution of MRI with specificity for these various cell types or biological processes that are going on. And a lot of people have been working on this, but to date that doesn’t really exist. And part of the reason for that is because the biological processes don’t occur in isolation. Lots of different things happen with inflammation – water moves around – and so it may actually not be possible to do that, but people are still working in that. So that’s a great challenge is to figure out how we could specifically assess inflammation, myelination, axonal health with imaging. But I don’t think that precludes us, again, from using the imaging either to help with the diagnosis, to assess new therapies, or to really observe and build stories about how the biology is working in the disease.   MSDF What’s happening in the cutting-edge of MS neuroradiology?   Dr. Reich I think the most exciting development in MRI and multiple sclerosis is the ability to look with greater and greater precision at what’s going on in the brain and spinal cord, and how that changes over time. And that is being made possible by really rapid advances in the technology. I think that will no doubt translate into the ability to better assess the course of an individual person’s disease, whether they’re responding to therapies, either immunomodulatory therapies that current exist or the reparative or protective therapies that will hopefully come online soon. And I think that’s tremendously exciting.   MSDF Do you also collaborate with people in other specialty areas in the course of your work?   Dr. Reich Yeah. Personally, I have many collaborations. I have collaborations with pathologists, I have collaborations with immunologists, with clinicians, with virologists, with other imagers. So for my work which really depends on understanding the intersection between the imaging we do and the biology of the disease, those collaborations are critical. Through our NAIMS Cooperative, the imaging group in North America that we’ve recently started, we’re hoping really to develop very powerful interactions among groups that have a lot of expertise in how to do imaging in multiple sclerosis.   So in addition to the standardization work, we’re very much hoping to be able to share techniques that we develop. And we’ve established a platform in which that is happening. We’re also hoping to use this cooperative group to sort of cross-pollinate the various labs to use it as a training forum so that the next generation of people interested in imaging and MS will, number one, get to know each other, but also learn from labs in which they don’t spend all their time. So it has a multipartite mission which hopefully will really drive the field forward.   MSDF Well, thank you for sharing your thoughts on MRI and MS with MSDF.   Dr. Reich It’s my pleasure.   [transition music]   Thank you for listening to Episode Thirty-Five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

[intro music]   Hello, and welcome to Episode Thirty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Seema Tiwari-Woodruff about estrogen in animal models of MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Last week, we reported on the results of another clinical trial for hematopoietic stem cell transplantation in relapsing-remitting MS. Compared to the “halt-MS” trial, which we reported on in January, this study used a less aggressive conditioning approach. Patients involved in the study demonstrated improvement in EDSS scores, and eighty percent of them were relapse-free at four years. The results raised important questions about how to prep MS patients for the transplant. Visit our “News and Future Directions” section to read the full story.   A recent study published in the Multiple Sclerosis Journal demonstrated a potential new way to monitor lesion repair using standard MRI techniques. Clinical trials usually look for new lesions in brain scans to monitor drug efficacy. Lead author, Daniel Reich, told MSDF it’s more important than ever to be able to visualize changes in tissue since drug development is shifting towards neuroprotection and repair.   We’re also pleased to announce that Daniel Reich is one of two new members of our Scientific Advisory Board. Dr. Reich is the director of the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. Our other new board member is Deborah Backus, an expert on rehabilitation who is Director of Multiple Sclerosis Research at the Shepherd Center in Atlanta, Georgia. Read their full bios in our “Who We Are” section under the “About Us” tab.   [transition music]   Now to the interview. Dr. Tiwari-Woodruff is an associate professor of biomedical sciences at the University of California, Riverside. She met with MSDF editor-in-chief, Bob Finn, to talk about her research on estrogen and multiple sclerosis.   Interviewer – Robert Finn Dr. Tiwari-Woodruff, welcome.   Interviewee – Seema Tiwari-Woodruff Thank you.   MSDF So what is the connection between estrogen and MS?   Dr. Tiwari-Woodruff It’s an interesting connection between estrogen and MS, because estrogen is actually a part of life in a way that our brains require it, our bodies require it at every moment of our life, I should say. Many years ago it was found that relapsing-remitting patients had less relapses when they were pregnant, and the causes of that was potentially estrogens – high levels of them – or progesterone or vitamin D. Many researchers went ahead and looked at those high levels of pregnancy estrogens called estriol and found that high levels of estriol were the reason why these women patients had lower levels of MS symptoms.   So eventually down the line, estrogens were parsed out of which estrogen was better. And it turns out that one type of estrogen, which is the estrogen of the alpha, is more immunomodulatory – it actually suppresses the immune response – and that is probably what makes MS symptoms better versus estrogens of the beta ligand was known not to have that much immunomodulatory effect; instead, it was actually directly neuroprotective. So estrogens of the alpha and beta both seem to have an effect on various cell types which are involved in multiple sclerosis.   MSDF So if estrogen seems to be protective in pregnant women with MS, why not just use estrogen, or an analog like estriol or estradiol, as a treatment?   Dr. Tiwari-Woodruff That’s a very good question. And, first, these therapies were thought that we were going to use those first, and a lot of clinical trials were going through with that. But what happens with high levels of estrogen is there are two things which are important to know. One is they have a feminizing effect, and the second one is they have a preponderance for causing uterine cancer or breast cancer. So you don’t want to stimulate those two types of cancer. So high levels of estrogen could be dangerous in that aspect. So that is why we don’t want to use that as potential therapy.   MSDF So you’ve done a lot of work with a specific estrogen receptor agonist called indazole chloride. First, tell me how you came upon this compound.   Dr. Tiwari-Woodruff So estrogens of the beta ligands are not just being looked at for multiple sclerosis, they were being looked at as a potential therapeutic for menopause – hot flashes included – rheumatoid arthritis, and other impairments like prostate cancer, etc. So there were quite a few chemists who were coming up with various different types of estrogen receptor beta ligands. So while I was doing my work with mouse models of MS in generic estrogen receptor beta ligand, which was the DPN – diarylpropionitrile – a study came out which was actually on indazole chloride which was developed by a chemist, John Katzenellenbogen; he’s done a lot of work on developing these molecules. And this particular compound showed that it decreased activation of astrocytes and microglia; this was published in Cell a few years back. And we met at a meeting, John Katzenellenbogen and myself – we were giving a talk at the same time in a meeting in Stockholm – and we decided to talk to each other. And he said, “Your research is very intriguing on estrogen receptor beta ligand, would you like to try this out?” And that’s how I got my hands on the indazole chloride. And we did some preliminary studies and showed good results. Then we decided to embark on a full-fledged study which was published in PNAS.   MSDF So you used indazole chloride in two different mouse models of MS, and you used it both prophylactically and in mice that are already showing symptoms. What did you find?   Dr. Tiwari-Woodruff So prophylactically when you use a compound, you are actually trying to see if you can inhibit the symptoms which are going to come up when you induce a disease, and that is all good. But when you are talking about patients who come to see the doctor, they’re always coming in with symptoms, so they already have the disease ongoing. So the second paradigm where you give the drug when the disease symptoms are already there is closer to what humans are going to be able to see. So the nice thing about indazole chloride was that, prophylactically, definitely it made the mice better, but therapeutically also; they were able to decrease the disease symptoms by nearly 50%.   MSDF What is the significance of the fact that it seems to work on two different mouse models of MS?   Dr. Tiwari-Woodruff So when you’re looking at a drug especially in a disease like multiple sclerosis which has two major components – one is inflammatory component and another one is a neurodegenerative component – if you can show that this drug is working in one way or both ways would be very useful for developing better drugs or better treatments. So what we did was when we treated the mice with indazole chloride, in one mouse model which is the experimental autoimmune encephalomyelitis which contains both the inflammatory and the neurodegenerative component, we saw a decrease in the disease symptoms. But we couldn’t tell if the indazole chloride was working in the inflammatory component or the neurodegeneration component, because it showed effect on both.   So we went to a second mouse model which is the toxic cuprizone diet model which doesn’t have a primary inflammatory component. The disease starts with oligodendrocytes, the cells which make the myelin. They die when you feed this diet to the mice, so they have massive demyelination in regions of the brain. When we gave the drug during the remyelination phase, we found that indazole chloride was able to remyelinate the axons better when the drug was present versus when it was absent. So this actually showed us that indazole chloride has two arms to it. One, it inhibits the inflammatory component and the second, it inhibits the neurodegenerative component independent of the inflammatory component.   MSDF Is it also sort of confirmatory? The EAE is not a perfect model of MS and neither is the cuprizone mouse model, but does it make you feel better that these two completely different models are showing similar effects?   Dr. Tiwari-Woodruff Absolutely, you really hit the point where… We are always looking for the best model for multiple sclerosis, but because the disease is so complex no one model can be said that it’s 100% mimicking multiple sclerosis. So for us to see that demyelination which occurs both in EAE and the cuprizone model was improved – we actually saw remyelination in both models – really gave us hope that this drug could be directly acting on oligodendrocytes which are forming the myelin, which is the cause of major mode of dysfunction in multiple sclerosis.   MSDF So does indazole chloride help these mice a little bit, or does it help them a lot?   Dr. Tiwari-Woodruff So that’s a very good question. Similar to what you might see in the patient population, in the mouse model of MS, especially in the EAE model, the disease is not consistent. So the lesions which appear in the brain of EAE animals are very diverse, unlike the cuprizone model where the demyelination is very consistent. So when you’re looking at these mice, especially in the EAE cohort, if the animal is really, really sick, you actually see the disease symptoms go down just a little bit. But if the animals were sick to the middle level, they actually showed a bigger difference, they showed better recovery. And we hypothesize that the axons which have been injured to the point of no return, if the axons have been demyelinated and injured, it doesn’t matter now when you give them therapeutic drugs, these are not going to improve. So there are certain number of axons in the brain which drop out and we don’t see recovery in those. But said that, overall we still saw a significant increase with indazole chloride treatment in both models.   MSDF Have you done histology?   Dr. Tiwari-Woodruff Yes. We’ve done histology, we’ve done electron microscopy. And we do one more thing my lab is very good at, we do electrophysiology. Because one of the things we always think is when you look at remyelination you can see myelin coming up, but is the myelin functional? If the axons can conduct faster or better, then you know that the myelin which has covered the axons is functional. So we do all three. And we also include behavioral testing. So one of the tests we included which a lot of people use is a Rota rod; it’s a motor test to show that the mice can stay on the Rota rod much longer after treatment with indazole versus just the vehicle.   MSDF Do you see any side effects?   Dr. Tiwari-Woodruff So that’s interesting. We did not see any side effects in these mice. Agreed, we treated them up to 60 days, we haven’t treated them longer than that, plus we were giving them at a 5 mg/kg/day concentration. So we didn’t see any kind of toxicity. But said that, we still need to do those studies in a thorough way before we can safely say that they had no side effects.   MSDF So what’s next in the development of indazole chloride as a potential MS treatment?   Dr. Tiwari-Woodruff So indazole chloride is a good target. And while these studies were going on last year, John Katzenellenbogen and myself, we were talking about how are we going to proceed with this because we were seeing really good results; this is even before I published the paper. And he said what would you like to do? And one of the things we said was is it possible to make better analogs of this compound which are going to be more specific, could be used in a lower concentration and may have a better therapeutic outcome?   So he came up with four analogs which he has sent to me, and we did some preliminary studies to see if they were toxic to cells in culture, because that’s the first thing you do. And they have no toxicity in cells, they actually have shown to behave well with proliferation – depreciation of the cell – and we haven’t seen more cell death or less cell death with them. So we are very excited about that. So coming next month, we are actually going to start treatment of EAE animals, and once that goes through the goal is to do toxicity studies on the two best compounds and see if we can find a company so we can have a backing on these drugs for potential human trials. It’s a couple years from now, at least – it could be even more – but we are actually moving in that direction.   MSDF Dr. David Baker in a commentary on his multiple sclerosis research blog seemed less than enthusiastic about indazole chloride. He suggested that many compounds seem to work similarly in mouse models. How do you respond to that criticism?   Dr. Tiwari-Woodruff So Dr. Baker has a very good point on saying that there could be many compounds which are good in EAE but they fizzle out and they don’t go up to clinical trial. I disagree on one point where it comes to indazole chloride, because we have precedence of estrogens showing good therapeutic indication in humans; there were clinical trials done in UCLA where they showed that there was improvement with estriol treatment. And estriol does target both ER-alpha and ER-beta – ER-beta a little more than ER-alpha – so I’m very confident that what we are seeing with estrogen receptor beta is not a fluke. And because it’s a steroid and a small molecule, it does not seem to have a lot of toxicity involved which could be somewhat which is brand new. So we’ll see. I hope Dr. Baker’s wrong and we do manage to get this drug to human patients and we see therapeutic efficacy in them.   MSDF Dr. Baker also said that a critical experiment had not yet been done. And let me quote from his blog post. He said, “The development of demyelination should be allowed to occur after this damage has abated, then punitive remyelinating drugs should be given.” How do you respond to that?   Dr. Tiwari-Woodruff Very good point made by Dr. Baker, but I have actually addressed those in the PNAS paper. We part off particularly this aspect of the disease. So the prophylactic treatment was before the disease started; that is what he’s mentioning in the blog. The second part is what is important where EAE disease was induced, and after peak disease had occurred we gave the drug, indazole chloride. At the peak disease, we actually see increased inflammation, but alongside with that we see demyelination and axon degeneration. So the damage has already started. The drug treatment after that is what caused the disease to get better. We saw increased conduction, we saw increased remyelination, and less axon damage.   Similar to that, we also did the experiment in cuprizone. The treatment paradigm was as such: We actually had nine week of demyelination ongoing in the cuprizone model, which is very chronic; it’s chronically ongoing where you have quite a bit of damage of the axons and you have acute demyelination. During the remyelination phases where we gave the drug either to one group and vehicle to the other group, what we saw was that the drug treatment, indazole chloride, actually increased remyelination and decreased axon damage. So I think Dr. Baker was trying to make a point on we haven’t done the right experiment, but I think we have done the right experiment. And further research with indazole chloride will let us know if this is a good drug or not.   MSDF Dr. Tiwari-Woodruff, is there anything you’d like to add?   Dr. Tiwari-Woodruff I would like to add one more thing. We have actually looked at indazole chloride in optic neuritis – EAE-induced optic neuritis – and we are going to be publishing a paper fairly soon showing that in optic neuritis we see less inflammation in the retina and increased remyelination in the optic nerve. So I’m very confident that it’s not just a phenomenology in one part of the brain which we picked last time – it was the corpus callosum – that we see increased remyelination and decreased damage caused by EAE with treatment of indazole chloride.   MSDF Well, thank you very much.   Dr. Tiwari-Woodruff Thank you.   [transition music]   Thank you for listening to Episode Thirty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]