Podcasts about episode forty

Episode Forty-one features painter Dominic Chambers. He is an African-American artist from St. Louis, MO. Chambers received his BFA from the Milwaukee Institute of Art and Design and received his MFA from the Yale University School of Art. Chambers creates large scale paintings and drawings that reference literary narratives cited in books he’s read, various mythologies, and African-American history. His current work is invested in exploring moments of contemplation and meditation through reading and leisure. Chambers has exhibited his work in both solo and group exhibitions regionally and internationally. Chambers also has been the curator of exhibitions at the Kravets Wehby Gallery in New York and the Pitch Project in Milwaukee, WI. He has also participated in a series of residences including – The Yale Norfolk summer residency and the New York Studio Residency Program in Brooklyn, NY. http://www.dominic-chambers.com/ https://www.juxtapoz.com/news/magazine/features/dominic-chambers-magical-realism/ https://www.culturedmag.com/painter-dominic-chambers-opens-up-about-his-process-and-what-hes-been-making-in-quarantine/ https://www.lucegallery.com/work/dominic_chambers.html https://aacc-awc.org/ Photo credit: Joey Kennedy

Episode Forty features Peg Alston. For nearly four decades since establishing Peg Alston Fine Arts, she has emerged as this country’s foremost private dealer specializing in works by African American artists and other artists of African descent, as well as select pieces of traditional African sculpture. In addition to handling art created by gifted emerging and mid-career artists, Peg Alston has sold works by some of the most renowned 20th Century Black masters, including Aaron Douglas, William H. Johnson, Laura Wheeler Waring, William T. Williams, Horace Pippen, Charles White, and Elizabeth Catlett. She has also sold works by some of the leading names on the contemporary scene, among them: Sam Gilliam, Richard Yarde, Betye Saar, Howardena Pindell, Frank Bowling, Ronald Burns, Edward Clark, David Driskell, Al Loving, Lubaina Himid, Oliver Johnson, Faith Ringgold, and Raymond Saunders. Peg Alston emerged on the New York art scene in 1972, a time when art by African Americans was limited. Early giants such as Romare Bearden and Norman Lewis generously served as informal mentors during the beginning stages of her career. Thanks to her keen eye and tastes, commitment to her specialty, and dedication to educating the public through lectures and activism, she has played a pivotal role in cultivating an interest all around the country for investing in African American fine art, and formed close associations with many of today’s most important African American artists. Long active with theStudio Museum in Harlem and many other major New York City cultural institutions, Peg Alston organized some of the first seminars on collecting, appraising and cataloguing African American art. Today, Peg Alston is a member of the Private Dealer’s Association (PADA) and ArtTable, and recently had the honor of being interviewed by History Makers for their visual and oral archival collection. http://www.pegalstonfinearts.com/ https://www.thehistorymakers.org/biography/peg-alston-41 https://www.instagram.com/pegalston/?hl=en

* Episode Forty! * Any ideas on one-year anniversary special? * Any ideas for spreading the word about Earthdawn? * Email from Lee: Windling Archer and weapon selection? * Link to Fang from the Developer’s Blog * Email from Kogorsi: Swordmaster feedback and Josh gets called out. * Email from Brandon: Magicians not killing? * How soon to provide thread items? * Western gunslingers as inspiration for Swordmasters? * Dual wielding? * Another Email from Lee: True Shot process? * Stopping Aim preventing actions? Timing? * Brief sidebar on Initiative. * Group pattern threads? * Email from Benito: Wood Skin providing Unarmed damage bonus? * Most Earthdawn movie? Casting? * Ghost Master Ritual? * Are t’skrang related to dragons? * Namegiver discussion: Obsidimen * Dan has a lot of obsidiman characters. * Asexual, not necessarily agender or aromantic. * “To learn and appreciate all things.” * Have biological need to eat, sleep, breathe, etc. * Massive beings, half-ton. Like trolls world not often made for them. * No infantile or child-size stage of life. * Often contemplative, unassuming, deliberate, even-tempered. * Nature and trees are often sacred to obsidiman. * Liferocks and obsidiman birth and life. * Ultimate role-playing challenge in Earthdawn. * Discussion of obsidiman attributes. * Dexterity penalty, very large Strength bonus, Toughness bonus. * Slow movement, low Karma. * Limited to living armors. * Obsidimen stand out as one of the more unique aspects of Earthdawn. * Great choice for seasoned players looking for a role-playing challenge. * Champions’ Challenge Kickstarter. Email: edsgpodcast@gmail.com Twitter: @EarthdawnG Josh on Twitter: @mataxes Dan on Twitter: @boice_voice Get product information, developer blogs, and more at www.fasagames.com FASA Games on Facebook FASA Games Discord Channel Earthdawn Guild Facebook Group Earthdawn West Marches

The final story arc of Season 6 of The Clone Wars was a dense one! We have the return of Sifo-Dyas, an appearance from Darth Bane, Dagobah, how one becomes a force ghost, a Yoda solo adventure and Qui-Gon Jinn all included! We also find out just how big of a narc Ki-Adi-Mundi is, who was expecting the Yoda inquisition, how much it would hurt to step on a Lego Lumpy, plus all the long-reaching ramifications this arc has on the Skywalker saga! Turn up your headphones, dial back your sensibilities, and join the wretched hive of scum and villainy as we take the low road to resistance on Episode Forty of Force Insensitive!Send Email/Voicemail: mailto:forceinsensitive@gmail.comStart your own podcast: https://www.buzzsprout.com/?referrer_id=386Use our Amazon link: http://amzn.to/2CTdZzKFB Group: https://www.facebook.com/groups/ForceInsensitive/Twitter: http://twitter.com/ForceNSensitiveFacebook: http://facebook.com/ForceInsensitiveInstagram: http://instagram.com/ForceInsensitive

Welcome to Episode Forty of Strange Pleasures Radio Lab. Your daily audio story podcast available through iTunes, Spotify, Stitcher, Luminary and YouTube.Please support the channel by subscribing, rating and reviewing on your preferred platform.Today I will be narrating Part Fourteen of Frankenstein by Mary Shelley.YOUTUBE: https://www.youtube.com/channel/UC8MoqBN8-vdAsaoYBZX32OA?viewas=subscriber?subconfirmation=1HOME WEBSITE https://strange-pleasures-radiolab.pinecast.co/STITCHER https://www.stitcher.com/s?fid=465249&refid=stprLUMINARY https://luminarypodcasts.com/listen/robert-knight/strange-pleasures-radiolab/7805fc0b-96a1-45d0-88d0-19244c9b3312SPOTIFY https://open.spotify.com/show/6x2VOcohjOKeJ8ZIJpvi8rAMAZON AUTHOR PAGE https://www.amazon.co.uk/Robert-Knight/e/B07WH3QCML/ref=dpbylinecontpopebooks_1ITUNES https://podcasts.apple.com/gb/podcast/strange-pleasures-radiolab/id1476208251STRANGE PLEASURES VIDEO LAB: gaming channel with new content daily https://www.youtube.com/channel/UC0wqchZzHfwHTUdfnc5s6ggSupport Strange Pleasures Radiolab by donating to their Tip Jar: https://tips.pinecast.com/jar/strange-pleasures-radiolabFind out more at https://strange-pleasures-radiolab.pinecast.coThis podcast is powered by Pinecast.

Episode FORTY! We've hit mid-life crisis folks. STAR WARS GALAXY'S EDGE!!!!!!!! Also CAPTAIN MARVEL, Detective Pikachu, POKEMON SWORD AND SHIELD, and The Division 2. So much HYPE. Be sure to follow us here and on Twitter and Instagram for more Good Content™ — @whatthefuncast.

EPISODE FORTY-a: 2018 HALLOWEEN SPECIAL It’s finally Halloween, and time for our three-person discussion panel, featuring Alyson Fitch-Safreed and Dalton Hughes, to do something special – for our Halloween Special! Come listen, if you dare…or if you’re just really, really bored, of course. If you’d like to hear more of this sort of quality content, please come visit our Patreon page! It's at https://www.patreon.com/DWTargetBC. As a Halloween special, if you decide to join our Patreon at any level by 11:59pm CST on Thursday, November 22, the night before the 55th anniversary of DOCTOR WHO, you’ll be eligible to win one of the two copies of the book we’re discussing in our Halloween special (but you’ll have to listen to the episode to find out what book we’re doing – spoilers!). We now have a book discussion group of our very own on Goodreads! It can be found at https://tinyurl.com/y7kmaspr. If you want to have your question, discussion, or review of a given book read aloud by us, simply join the group, post your response to the group by the given deadline, and we will see it! If you really like us or feel the exact opposite, feel free to comment on our Facebook page or our Subreddit, follow us on Twitter (we’re @DWTARGETBC), or subscribe to us via the podcast provider of your choice (we can be found on iTunes, Soundcloud, Stitcher, and TuneIn, amongst many others)! Videos to accompany our first ten episodes can still be found on YouTube! You can also email us at DWTARGETBC@gmail.com. The Halloween sound effects in this episode can be found at https://www.youtube.com/watch?v=yl1Ez0Q2Q9U&t=2997s The wonderful “incidental music” for this episode comes courtesy of Inner Peace, at https://www.youtube.com/watch?v=wP8_mhRkkfc Facebook: https://www.facebook.com/DoctorWhoTargetBookClubPodcast/ Reddit: https://www.reddit.com/r/DWTargetBC/ iTunes: https://itunes.apple.com/us/podcast/doctor-who-target-book-club-podcast/id1195364046?mt=2 SoundCloud: https://soundcloud.com/doctorwhotargetbookclubpodcast Stitcher: http://www.stitcher.com/podcast/doctor-who-target-book-club-podcast TuneIn: http://tunein.com/radio/Doctor-Who-Target-Book-Club-Podcast-p957128/ Twitter: https://twitter.com/DWTARGETBC Goodreads: https://www.goodreads.com/group/show/710804-doctor-who-target-book-club-podcast

Episode Forty-three of the IdeaPod. In this episode, we discuss the Latest & Greatest: we talk about how KFC UK handled the PR disaster of its stores not having chicken forcing hundreds of stores to close as a result. Adweek ... Read More The post #43 Kentucky Fried What? appeared first on Bandwidth Marketing.

Episode Forty of  the IdeaPod. In this episode, we discuss the Latest & Greatest: we talk about our favorite ad from the Big Game because the ads and the food are the best part. Check out the ad we discuss ... Read More The post #40 Bathroom Break’s Over it’s Time for the Ads appeared first on Bandwidth Marketing.

Episode Forty features friend and sometimes co-host when it's convenient for him, Disco Dracula. This one is a blast from the past with some personal storytelling and reddit conversation to start it off, leading to a hodge-podge of assorted Relatable-Goodies when it comes to other DD episodes.A Warning to Those Thinking about Accessing the Shadow Web(16:25)SuicideMouse.AVI(33:00)The Episode of Nickelodeon's Double Dare that Will Never be Aired in the United States(41:49)Dead Bart(49:25)Pearl gets Herself Dead(1:00:00)Abandoned by Six Flags(1:05:30)Check out our episodes on Youtube!https://www.youtube.com/channel/UCxoqIN-fkfdlmGEjWujypxwFeaturing wonderful ambient music from our fam in Sweden: CryoChamber, givin' us all the ooky-spooky tunage. Follow: @cryo-chamberThank you!"Are You Afraid of the Dark Theme Song," "Spooky Skeletons REMIX," and "You Reposted in the Wrong Neighborhood" are not my songs. Credit and All rights are reserved by the owners

Conor O’Toole rates and reviews ground coverings this week. What’s so good about grass and why does he hate sand? Listen in to find out. Also this week – Leaving Cert Mystery Shoppers, Seeing-Eye Velociraptors and Walking Stick Martial Arts. It’s Episode Forty of Reviewables and We’re Using A Lot of Capital Letters! Conor is […] La entrada Reviewables #40 | Ground Control with Conor O’Toole se publicó primero en Headstuff.

Episode Forty-four is here to ROCK you to the core!! Nathan’s been galavanting around China and dreaming about the demise of his co-host, while Jon’s been boozing it up and binging yet another tv show. Find out all about it in this week’s What Chu Been Up To? In GAME TIME we return to a simpler, … Continue reading #44 – #TBT The Era of Nickelback…Oh God. →

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Hugh Rosen of the Scripps Research Institute. But first here are some new items in the MS Discovery Forum.   If you’re an MS researcher, you may want to keep an eye on our Bulletin Board section, where we post a variety of news items that may be of interest. One of the items we posted this week is directly related to Dr. Rosen’s work. It’s a notice that a phase 3 trial of a sphingosine 1-phosphate receptor modulator called RPC1063 has started recruiting twelve hundred patients with relapsing remitting MS in the US. RPC1063 had its origins in Dr. Rosen’s lab.   We also recently added a notice of another clinical trial to the Bulletin Board. That one’s a phase 2 trial of oral laquinimod in primary progressive MS. And a third new Bulletin Board announcement is a request for information from the Patient Centered Outcomes Research Institute to identify patient registries and research groups with established cohorts of patients for potential collaborative research opportunities on comparative effectiveness research in MS treatment.   To read any of these announcements, go to msdiscovery.org and click first on Professional Resources and then on Bulletin Board. And if you have an announcement you think may be of interest to MS researchers, please send it to editor@msdiscovery.org. We won’t post purely promotional press releases, but if we judge the notice to be of general interest, we’ll be happy to post it at no charge.   In other news, it was a relatively slow week in published MS research. According to our curated list of the latest scientific articles related to MS, only 22 such articles were published last week. Typically at least 40 MS-related peer-reviewed articles are published weekly, and we’ve seen some weeks with more than a hundred. To see the weekly lists going back to March 2012, go to msdiscovery.org and click on Papers.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 2 new trials and 7 other pieces of information. The drugs with important additions are dalfampridine, fingolimod, masitinib, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hugh Rosen studies chemical and biological approaches to the molecular mechanisms regulating lymphocyte trafficking. I met with him in his office at the Scripps Research Institute in La Jolla, California.   Interviewer – Dan Keller We're talking about mostly new compounds, S1P1 receptor compounds; the prototype now I suppose is fingolimod. What's in development and do they appear to offer advantages?   Interviewee – Hugh Rosen So, firstly, let me disclose that I am a cofounder of a biotechnology company called Receptos that has licensed an S1PR1 agonist from the Scripps Research Institute, so I have and my institution have a significant interest in this particular field.   Sphingosine 1-phosphate receptors act in a number of ways to modulate immune tissue damages in both autoimmune diseases and in viral infections. They've proven to be particularly efficacious in multiple sclerosis. Gilenya, of course discovered by Yoshitomi in Japan and developed by Novartis, has proven to be a clinically useful compound in the treatment of relapsing-remitting multiple sclerosis. And it appears to do so, at least in part, by altering the ability of lymphocytes to recirculate, and thus lymphocytes to reach the target tissues where they, in fact, produce demyelinating damage to the white matter of the central nervous system, and then the signs and symptoms of multiple sclerosis. So clearly these are useful compounds.   Gilenya, of course, is not a selective small molecule, it is an agonist of four of the five high affinity receptors for sphingosine 1-phosphate – S1P1, 3, 4, and 5 – and some of the associated side effects may be attributable in part to activity of Gilenya on other receptors like the S1P3 receptor that are not required for modulation in the treatment of multiple sclerosis.   MSDF I see that it's referred to as an immunomodulator, not necessarily referred to as a receptor agonist. Does it not have pure agonist effect? Does it have any effects either because of the other receptors or at that same S1P1 receptor?   Dr. Rosen No. In fact, Gilenya when phosphorylated is a full agonist of the sphingosine 1-phosphate receptors, and the newer compounds that are much more selective are also agonists of the sphingosine 1-phosphate 1 receptor. And some of the effects on them for cyto-mediated by downmodulation of the receptor, but I don't use the term modulators or immunomodulators because of the activity on the sphingolipid receptors per se, I use the term immunomodulator because of some of the unique advantages that we've demonstrated in model systems and in man about altering the activity of the sphingosine 1 receptor, because one of the beauties of immunomodulation is to blunt the immune response that causes collateral damage to the tissues whilst leaving sufficient of the immune response intact to allow protection from opportunistic pathogens – bacteria, viruses, and yeasts.   So one of the most striking features that we found – and these have been in some experiments done as a collaboration between my laboratory and the laboratory of Professor Michael Oldstone here at Scripps – has been in the area of influenza; pandemic influenza causes significant collateral tissue damage by having an overactive immune response. What we show is that the sphingosine 1-phosphate 1 receptor blunts that immune response and blunts the amplification of cytokines and chemokines so that you protect from the collateral tissue damage, but you leave intact the ability to mount protective, sterilizing T cell and B cell immunity to the virus. So you can eradicate the virus, sterilize it, you can provide a long-term memory both on the T-lymphocyte side as well as on the antibody side; there's class switching, there's affinity maturation, there are good protective immunity that is produced, and all this while blunting the immune response.   This is the Holy Grail as we think about treating patients, because the window for patients with autoimmune diseases like multiple sclerosis is that window between effective blunting of the immune response and the prevention of deleterious opportunistic infections that can have life-threatening consequences. So one of the advantages that I suspect we will see over time is that the sphingosine 1-phosphate agonists will prove to be particularly well-tolerated and have a wide window between the ability to limit tissue damage and progression of RRMS, and the need to protect patients from intercurrent infections or subclinical infections that become expressed later.   MSDF Do the other sphingosine 1-phosphate receptors interfere with lymphocyte trafficking also, or do they have other effects which nonselective ligands would then induce these adverse effects through them, or do they also have some effect in terms of trafficking?   Dr. Rosen They don't have significant effects on lymphocyte trafficking the way that S1PR1 does, both from the chemical approaches and the genetic evidence. S1P1 is clearly a toggle switch for lymphocyte trafficking. S1P2 is involved in the maintenance of hearing and in the function of vascular smooth muscle, so it regulates blood pressure. S1P3 is involved in cardiac contractility and also in the control of coronary artery caliber and the control of the airways, so S1P3 agonism is not a useful thing, it's actually quite deleterious. S1P4 and 5 have really no rate-limiting functions, at least of which I am aware, so there may be some redundancy and may not play a critical role in the modulation of health and disease.   MSDF Do you see compounds coming along which will be more selective and therefore not lead to the adverse effects so much? And if so, are these compounds chemically similar or do they have different structures to attach to the receptor, the S1P1?   Dr. Rosen These are clearly different structures, they're structurally very distinct from Gilenya and from each other. Novartis have a backup called siponimod. Actelion had a compound but it's only being used in psoriasis called ponesimod. Receptos has a compound now known as ozanimod – formerly known as RPC1063 – that is in two phase 3 studies for relapsing-remitting multiple sclerosis, a two-year study called RADIANCE and a one-year study called SUNBEAM, both of which are enrolling twelve hundred patients each.   MSDF And the RADIANCE trial results looked pretty good; I mean, you had 85, 90% effects at 12 to 24 weeks or even at a year in terms of relapse rate. Does this look like the next compound to emerge?   Dr. Rosen I think it's likely that ozanimod will be the next compound to be submitted for the regulatory process here in the United States and probably in Europe as well. The pleasing thing about the phase 2 data for ozanimod was, in fact, both the strong efficacy signal and a very well-tolerated safety profile; in fact the adverse effect profile of ozanimod and placebo were, in fact, indistinguishable and overlapping in the phase 2 studies. In addition, this very well-tolerated, favorable safety profile has been replicated in a highly successful phase 2 study in ulcerative colitis called TOUCHSTONE that was released recently. So clearly this is a mechanism of immunomodulation that could well prove to be useful for relapsing-remitting multiple sclerosis, but also in a range of other autoimmune diseases where treatments are hard to come by.   MSDF Even with Gilenya, I think there have been reports of a couple of cases of progressive multifocal leukoencephalopathy, so it gives a nice balance between immune surveillance and inhibiting T cell trafficking, but it seems like not a perfect balance. Does it look like that margin will be narrowed in the future with other compounds?   Dr. Rosen It's possible that it will be. I think the critical point to bear in mind is that real-world experience in tens of thousands of patients with hundreds of thousands of patient-years is really ultimately what is required to define these very rare events that on occasions do occur, and preexisting treatments with other immune-modifying agents such as Tysabri, for instance, may predispose to issues being seen later with PML. And I think that we always have to say that long-term patient experience and physician comfort are ultimately the best guides to the risk-benefit ratio.   MSDF I think you've identified something like four compounds in development, those are some that I had seen. Are there others, or these are really the ones to focus on at this point for people to keep an eye on?   Dr. Rosen There may well be others that are further behind. There have been a number of others that have had safety signals, particularly liver enzyme elevations, and significant first-dose cardiac effects. Arena have a compound that has recently completed a phase 1 multiple-dosing study and will go on to phase 2. So, you know, there are additional compounds and there will be additional compounds. Ultimately, patients do best when the best compounds appear, and the only way one knows that is to test them in man over the long-haul and define that risk-benefits for patients. And, you know, these multiple efforts really reflect the fact that a field has advanced, and that advancing field really does improve through intelligent intervention our ability to offer patients a better set of choices and a better set of long-term outcomes, which is what we're all about.   MSDF We're still focusing here on RRMS, none of this applies to the progressive phase. Is there anything coming along there?   Dr. Rosen You know, there's been one trial in primary-progressive; this was the Gilenya trial which didn't meet its endpoints. It may be that the mechanisms in rapidly progressive MS are a little different and that we don't yet, I think, understand the pathogenesis of that rather different presentation. So I'm not aware of a good alternate approaches to that, but that doesn't mean that the understanding isn't there for that to happen over time, it simply means that I'm not yet aware of it.   MSDF Finally, in secondary-progressive MS, we can understand what's going on, what led to it; if you limit relapses, that's good. But does it look like primary and secondary really may be overlapping but not the same disease?   Dr. Rosen I think there may be balances of pathogenesis where you can intervene more easily in some than in others. Clearly the sphingosine 1-phosphate agonists work particularly well by inhibiting the movement of lymphocytes into the brain. The movement of lymphocytes from the perivascular cuff into the parenchyma, into the white matter, where the demyelination proceeds. However, in parallel in multiple sclerosis, there are also events where there is collateral damage to neurons; we see axonal severing, we see elements of neuronal loss. Certainly with the sphingosine 1-phosphate agonists, there is some evidence that there is a diminution of cortical thinning over time with treatment, and that may be a really good thing.   I think that the neurodegenerative components is one that is hard to get a handle on right now, and that I think that these differences will become more obvious with early treatments of the immunopathology of multiple sclerosis. And that may well separate the autoimmune inflammatory damage and its sequelae from neurodegenerative mechanisms that may be entrained, and I think we will learn a lot from looking at those subsets of patients over time, particularly as more, better, and earlier treatment modalities allow the avoidance of significant damage in most patients.   MSDF Is there anything important we've missed or you'd like to add?   Dr. Rosen You know, I think for all of us who try to work at this interface of therapeutics, we do so because disease is, in fact, personal. We all know patients, we've all seen the multigenerational impact and depredations of multiple sclerosis on friends and family. And I think this is the very strong underlying motivator that drives us as scientists and as physician scientists to really try and bear in mind that the basic mechanisms and the basic therapeutic approaches that we pursue ultimately need a safe and effective human face to change the lives of patients in a positive way.   MSDF Very good. Thank you.   [transition music]   Thank you for listening to Episode Forty-nine 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]   Host – Dan Keller  Hello, and welcome to Episode Forty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Bruce Cree on the EPIC, CLIMB, and SUMMIT clinical trials in MS. But first here are some new items in the MS Discovery Forum.   We're very happy to report that MSDF has received three generous grants that will allow us to continue our mission: to focus attention on what is known and not yet known about MS and related conditions in a way that builds bridges among different disciplines. Genzyme has given us two grants. One will allow us to continue producing this weekly podcast for another year, and the other will allow us to develop an additional 12 monthly data visualizations. And Biogen has given us a grant for general operating support. None of these grants will interfere with our editorial freedom, and you can continue to count on MSDF to be an independent source of unbiased MS news.   A conference in Cambridge, Massachusetts several weeks ago sponsored by Orion Bionetworks outlined the progress and challenges in turning computational modeling into actionable knowledge in MS and other brain disorders. Allison Provost, who is Orion’s scientific program manager, has written a blog post describing the parts of the conference of particular interest to MS researchers. You can find her post by going to msdiscovery.org and clicking first on News and Future Directions and then on Blogs.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected three of those papers as Editors’ Picks. Two of them are comprehensive review articles: one on biomarkers in MS and the other on MS immunogenetics. The third is an evidence-based consensus guideline on the use of MRI in MS diagnosis.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 1 new trial, we updated information on 3 other trials, and we added 13 other pieces of information.  The drugs with important additions and changes are alemtuzumab, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, and rituximab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to the interview. Dr. Bruce Cree is a neurologist at the University of California, San Francisco. MSDF Executive Editor, Bob Finn, caught up with Dr. Cree in his office at UCSF’s Mission Bay Campus shortly after a departmental seminar entitled “An EPIC CLIMB to the SUMMIT.”    Interviewer – Bob Finn Dr. Cree, welcome.   Interviewee – Bruce Cree Thank you.   MSDF Now EPIC, CLIMB, and SUMMIT are acronyms for three MS clinical studies. So first, what's EPIC, what's CLIMB, what's SUMMIT?   Dr. Cree Great question. So the EPIC study is a long-term observational study now in its 11th year at UC San Francisco. It's a a cohort study of multiple sclerosis patients who have been followed annually for the last 11 years. And this cohort initially had about 517 participants, and now – in its 11th year – we have about 91% of those patients coming back for ongoing assessments. The assessments include annual MRI scans, as well as clinical assessments and the blood draws for biomarker studies.   The CLIMB study is a similar related study that was developed independently at the Brigham and Women’s Children's Hospital in Boston under the directorship there of Howard Weiner. And it is also a long-term followup study. And now, after about seven years, that study has some 217 patients who have been retained out of the original cohort.    SUMMIT is the idea of bringing together long-term, well-curated observational cohorts from multiple sites. And the first iteration of SUMMIT will involve investigators from Basal, Amsterdam, UCSF, and Harvard who will merge together their long-term observational cohorts into a larger study. And the hope here is that we will obtain greater statistical power and be able to answer some of the more pressing questions about MS therapeutics, outcome measures, and utility of both conventional and nonconventional MRI in assisting with the diagnosis and management of patients.   MSDF So in the EPIC study, I'm struck by the fact that you've been able to retain 91% of your patients after 11 years; whereas in the CLIMB study they've lost 90% of their patients in just 7 years. How do you account for that difference?   Dr. Cree The EPIC study has had a great amount of support for long-term followup and subject retention. And we've gone to great lengths to keep our participants interested in the study and wanting to come back. And we have a terrific group of study coordinators who work day and night to maintain contact with our patients, inform them about why it's important for them to participate in the study. And we've even done outreach where we've gone to people's homes to perform evaluations in their homes where they were too ill to come in, as happens with multiple sclerosis as people develop more advanced disability. So we have very good retention as a consequence of the hard efforts made on behalf of the overall study by the coordinators and other members of the team.    MSDF Now you've used several measures of disease progression in the EPIC study, as have others in other studies. There's the EDSS, there's the MSFC, and there are several other measures. But let's talk about the EDSS first. That's probably the most commonly used measures, and it's also the one that people seem to love to hate.    Dr. Cree Yes.   MSDF Can you tell me about the EDSS and what its advantages and disadvantages are?   Dr. Cree Yeah, so the Expanded Disability Status Scale of Kurtzke is an ingenious scale that was really intended to describe where patients are at during the course of their lifespan. And it's a 10-point scale with half-point increment changes after the score of 1. And this scale has been adopted for use as the disability outcome measure in all MS clinical trials. The scale has a fair amount of inter-rater variability, which makes it challenging to administer. Because anytime you have a scale where there's a fair amount of variability it gets harder to interpret change. We did look at the EDSS systematically and looked at change over the first few years in the study and used that as a predictor for long-term disability transitions. We also looked at harder endpoints in the EDSS such as the time it takes for patients to go from no systems, disease onset, to the time where they require a cane to ambulate.    You mentioned the MSFC, the Multiple Sclerosis Functional Composite. This is a set of scales that were developed for use in multiple sclerosis that included the Timed 25-Foot Walk, which is a measurement of how fast somebody can walk 25 feet. That is clinically relevant because the speed at which somebody walks correlates quite well with the distance they can walk. So the faster you can walk 25 feet the longer you can walk. The 9-Hole Peg Test is a test of upper arm coordination and function. And the Paced Auditory Serial Addition Test is a test of cognitive function that measures specifically the tension and processing speed.    So we looked at these things, and we set up thresholds based on other clinical work that were considered to be clinically meaningful changes. So with respect to the Timed 25-Foot Walk and 9-Hole Peg Test, we were looking for a 20% worsening in function over the course of the trial. And with respect to the Paced Auditory Serial Addition Test – or PASAT – we were looking at the reliable change index for that outcome. And so these have been validated outcomes that are related to actual disability.   So we looked at all of these measures. And what we found was that when we looked at our relapsing MS patients about half of the patients experienced worsening in terms of EDSS change over 10 years. For the patients who had progressive multiple sclerosis, about 70% of them worsened. And then for these more stringent measures with respect to the MSFC components, we found lower proportions of patients with relapsing MS in secondary progressive or primary progressive disease had worsening in those outcomes, as well. So those were our endpoints for the study; they're clinical endpoints.   MSDF One of the things I noticed in your talk was that there was a great deal of overlap between the EDSS and the overall MSFC score; whereas there wasn't much overlap between the individual components of the MSFC score. What is the significance of that?   Dr. Cree Well the EDSS is itself a composite measure, and people tend to forget that. Especially earlier on in the scores that go from 0 to about 4, there you have 6 functional scale scores that contribute to the overall EDSS. That includes assessment of vision, brain stem function, motor function, sensory function, cerebellar function, bowel and bladder function, and cerebral function. And those separate functional scale scores are scored independently and then are summarized into an EDSS score between 0 and 4. After that, the EDSS score becomes really much more of an assessment of how far patients can walk until they have hit the major disability milestones of an EDSS of 6, which is walking with a cane, 6.5 a walker, 7 a wheelchair, or 8 bed bound.    MSDF So why is there a lot of overlap between EDSS and MSFC but not so much overlap between the components of MSFC?   Dr. Cree So when you look at the MSFC, you have two measures to the MSFC that are looking at motor function: the 9-Hole Peg Test and the Timed 25-Foot Walk. They can also be measures of cerebellar function. Both of things are very well measured in the EDSS by the functional scale scores for pyramidal and cerebellar function. The PASAT is not as well measured in the EDSS, although we have a cerebral functional scale score it's not a very precise measure, and there's a weakness associated with EDSS. Whereas in the MSFC, it's a very precise measurement.    When we look at the individual MSFC scores themselves, you can have patients who worsen in terms of walking, patients who worsen in terms of arm function, and patients who worsen in terms of cognitive function. And there is some degree of overlap in those three domains but not complete. And that just underscores how MS will affect different individuals differently. Some people have more ambulatory impairment, other people have more upper limb function impairment, and still other people have more cognitive impairment.   MSDF You made an interesting analogy to rheumatology in the treatment MS: the question of whether you should treat to no evidence of disease activity. I wonder if you can talk about that analogy and the NEDA, or no evidence of disease activity, goal.   Dr. Cree Sure. So in rheumatology in the 1990s, the discussion at that time had to do with how to treat rheumatoid arthritis. And this concept was advanced, which was a treat-to-target approach. The idea of using increasingly effective therapies to silence and suppress any evidence of active rheumatoid arthritis. And this strategy turned out to be extremely effective in treatment of rheumatoid arthritis. And instead of waiting for people to develop more disability, initiation of early highly effective treatments and really suppressing all joint inflammation became the current standard of therapy. And this has resulted in significant improvements in long-term disability in patients who are living with rheumatoid arthritis.    So taking that example and extending it to the field of multiple sclerosis, the idea here is that you have evidence of active multiple sclerosis on MRI scans such as gad-enhancing lesions and new T2 lesions; and evidence of relapses, which are clinical manifestation of acute inflammation; and disability progression, which is looking at the EDSS score and saying okay well if we have a combined measure that looks all of these things, and we try to suppress disease activity perhaps we're going to wind up with better outcomes. And so, this metric of no evident disease activity is defined as no evidence of relapses, no evidence of disability progression by the EDSS, and no evidence of MRI disease activity.    And it was originally developed in the context of clinical trials; specifically the pivotal trial of the natalizumab versus placebo study. And a certain proportion of patients in that study met this criteria of no evidence of disease activity. Subsequently, with more recent trials, other compounds have also been looked at and compared to their placebo or active comparator controls. And in each of these studies, you can see differences between treatments with respect to the proportion of patients with no evident disease activity.    The field of MS today is considering use of no evident disease activity as a therapeutic strategy or goal so that one would escalate therapy to the point where you see no evident disease activity. And the hypothesis here is that if you are able to effectively reach no evident disease activity that that is similar to putting patients in remission or preventing further disability from occurring. So we were very interested to find out whether there was long-term prognostic value of this marker, no evident disease activity.    And so, within the EPIC study, we looked at no evident disease activity over the first two years of the trial, and there was a proportion of our patients from this study who met those criteria: who had no change in terms of disability, no change in terms of clinical relapses, and no evidence of active multiple sclerosis by MRI scan. And we thought that that group would have a better outcome overall than the rest of the cohort. To our surprise, we found that there was no predictive value of no evident disease activity on any of the clinical markers that we looked at for 10 years.    So these patients had exactly the same risk for disability progression as patients who had evidence of active multiple sclerosis. And this was very perplexing; we just didn't really understand why that would be the case until we really started to look at the impact of treatment and use of escalation therapy in our cohort. And I think that when you look at the influence of therapeutic intervention in multiple sclerosis the effect size of therapeutic intervention is so great that other markers of biological disease activity such as new lesions wind up being minimized by the therapeutic impact. And as a consequence, things that might have been predicted based on natural history studies – such as brain volume loss, new lesions – become less apparent as having clinical meaning over a 10-year period of time because of the dominant influence of therapeutic intervention.    With respect to the no evidence disease activity, one of the questions that I think needs to be answered is do we really have the best markers for this? And if we are going to use a treat-to-target approach, are the things that are currently being looked at in no evident disease activity the right things to look at? And there is now interest in looking at other markers, as well, looking in incorporating, for example, brain volume into the no evident disease activity. And it will remain to be determined whether other ways of looking at no evident disease activity wind up performing better as a long-term predictor.   MSDF So when you're confronted with an individual patient – a new patient early in their course of disease – every neurologist is confronted the question of whether you start them with an interferon and escalate as they progress, or whether you start them with a highly active therapy. How do you make that decision, and how does the evidence from EPIC inform that decision?   Dr. Cree That's a great question, and I think this is probably one of the most provocative aspects of this long-term study. In EPIC, we used the escalation strategy where we began with so called platform therapies; drugs that are used as disease-modifying therapies that have been around for a long time, specifically the interferons and glatiramer acetate. And in the event that patients experienced relapses or had other markers of worsening such as brain volume loss, many of those patients were escalated onto what we would consider to be high-potency therapies. Drugs like natalizumab or medications that are off-label but still used in treatment of multiple sclerosis like rituximab or cyclophosphamide.    So we used this escalation strategy in this cohort. And what we found was the following. Treatment escalation was not associated with improved outcomes. In fact, treatment escalation was associated with worse outcomes in some patients. Now, why would that be the case? Well there's probably a confounder there of the indication to treat so that the patients who were getting escalation therapy are doing worse, and so they get the escalation therapy. So what we don't know from this study is if those patient hadn't gotten escalation therapy how would they have fared? We can't answer that question. That would require a randomized controlled trial.    But what this study does provide is this provocative idea that perhaps escalation therapy was really too little too late. That we were identifying a group of people who were at high risk of disability progression, but we weren't really setting things back to restore them onto a normal pathway and certainly not to prevent long-term disability. And this raises the idea that perhaps we should be utilizing these higher-potency therapies earlier. Now, that type of approach – the maximal efficacy approach – doesn't have data yet to support its use, but there are a few provocative studies that suggest that high-potency therapy might be associated with better outcomes. And we have the recent results of the cladribine study in clinically isolated syndrome where we had the best data yet for use of a broad-spectrum immune suppressant in terms of venting, time to the next clinical or radiographic event in patients who have presented with a first demyelinating event. And that study out performed all prior trials in clinically isolated syndrome so raises the question should be using an aggressive therapy right from the get-go?   And then, we have the alemtuzumab pivotal trial where alemtuzumab was compared head-to-head versus interferon beta-1a twice weekly in newly diagnosed patients. And in that study, alemtuzumab also out performed interferon beta-1a on many of the short-term markers of inflammatory disease activity. And we recently saw long-term data with alemtuzumab indicating that those patient do really quite well over a four-year period of time. So actually midterm data.    So we have a few lines of evidence to suggest that perhaps we should be using these high-potency therapies earlier. What we don't know is the relative risk-to-benefit profile. Certainly these higher-potency therapies carry greater risk to the individual subjects who are treated with these medications. And what we ultimately have to determine is whether those risks at a population level are worth the potential benefits of using a greater potency therapy early on in the course of MS.    It's my opinion that it's unlikely that the pharmaceutical industry is going to answer this question for us definitively. This type of approach to compare escalation therapy to high-potency therapy or maximal efficacy therapy from the get-go will require quite a bit of time of followup – at least five years if not longer – and will require large studies. So it seems to me unlikely to be endorsed by the pharmaceutical industry. It also seems unlikely that it's going to be sponsored by national organizations such as the National Institute for Neurological Disease and Stroke because of the extremely high costs associated with this type of clinical trial.    So that raises the question how are we going to answer this pressing unmet and unanswered question? And I think observational studies such as EPIC will be able to do this when merged together with other long-term followup cohorts. Today we have treatments that we didn't have 10 years ago, for example, fingolimod, dimethyl fumarate, alemtuzumab. These medications are currently being used in clinical practice. And I think we should be responsible for aggregating data on the patient experience with these medications, putting it into a systematized process for analysis, and aggregating this type of data across multiple centers. And that really is the goal of SUMMIT, which is going to involve pooling together our patient experience with our existing cohort, as well as new cohorts from UCSF, from Harvard, from Basal, from Amsterdam, and hopefully from many other MS centers as well. And then, with that pooled data, we'll hopefully be able to answer this question in a meaningful way.    MSDF Well, Dr. Cree, thank you very much.    Dr. Cree My pleasure.    [transition music]   MSDF Thank you for listening to Episode Forty-eight 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]   Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the Association of British Neurologists on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS.   Interviewer – Dan Keller What's interesting there at this point?   Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated.   Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system.   So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS.   The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons.   And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes.   We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease.   So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system.   MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens.   Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system.   MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state?   Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system.   MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days.   Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat.   MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats?   Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain.   MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control?   Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on.   What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet.   [transition music]   MSDF Thank you for listening to Episode Forty-seven 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]      

Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy.   Interviewer – Dan Keller Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now?   Interviewee – Hans Lassmann Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic.   MSDF Can you give me some examples of these kinds of antibodies?   Dr. Lassmann So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration.   Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis.   It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica.   So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients.   MSDF It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO?   Dr. Lassmann This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen.   There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven.   MSDF But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base?   Dr. Lassmann No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies.   MSDF Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not?   Dr. Lassmann So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein.   And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis.   However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children.   In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis.   Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes.   MSDF Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod?   Dr. Lassmann These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently.   MSDF Are there separate etiologies, does it look like here, the MOG versus classical MS?   Dr. Lassmann This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known.   MSDF Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade?   Dr. Lassmann This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis.   MSDF Anything interesting or important to add on the subject, in this context?   Dr. Lassmann I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy.   MSDF Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common?   Dr. Lassmann I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures.   This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen.   This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies.   MSDF Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions?   Dr. Lassmann It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect.   Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly.   MSDF Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones?   Dr. Lassmann This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans.   [transition music]   Thank you for listening to Episode Forty-six 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]   Host – Dan Keller Hello, and welcome to Episode Forty-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 Dr. Simon Hametner, who discusses the role of iron in multiple sclerosis. But first, here are some of the new items on the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 59 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, published in Nature Reviews Neurology proposes a definition of aggressive multiple sclerosis as well as a treatment algorithm. The other editor’s pick, published in the journal Neurology, reports on a randomized, placebo-controlled study on patients switching from natalizumab to fingolimod, concluding that shorter washout periods may be better.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 3 new trials, we updated information on 2 other trials, and we added 9 other pieces of information. The drugs with important additions and changes are daclizumab, dimethyl fumarate, fingolimod, interferon beta-1a, laquinimod, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Simon Hametner works with Hans Lassmann at the Medical University of Vienna in Austria. We spoke about iron accumulation in MS in cells of the central nervous system and what iron may be doing.   Interviewer – Dan Keller Let's talk about iron and neurodegeneration. What specifically are you looking at?   Interviewee – Simon Hametner We are looking at the formalin-fixed, paraffin-embedded brain tissue from multiple sclerosis patients and controls, and we're looking, for example, at iron in these tissues. We're also looking now at proteins which are engaged in the management of iron in these tissues, for example, now.   MSDF What are you finding different in MS patients that you don't see in healthy people?   Dr. Hametner So we see iron accumulation, for example, in microglia and macrophages in MS, which are related to MS lesions. There are, for example, some MS lesions which have macrophages around those lesions, and we don't see much of iron in macrophages and microglia in healthy control tissue. We also see iron loss in multiple sclerosis because the iron is normally stored in oligodendrocytes in the controls. And this is also the case for MS, but in MS we also see a loss of this iron in the oligodendrocytes, especially at the oligodendrocytes which are closed to MS lesions.   MSDF Do you know the mechanism of why you're seeing these differences in iron?   Dr. Hametner We are now performing the research to find about these mechanisms. We have some prior indications, for example, hephaestin upregulation on oligodendrocytes in the vicinity of the lesions, but these data were not so straightforward. We are now also looking for ferroportin; ferroportin is an iron exporter of glial cells, it's actually ubiquitously expressed in mammalian cells. And all the glial cells also can express ferroportin, and we found it also in the oligodendrocytes; we now undertake this research. We think that oligodendrocytes really upregulate ferroportin and hephaestin in order to export iron.   MSDF Is the iron detrimental?   Dr. Hametner It depends. We don't think that it is, per se, detrimental; we see loads of iron in the deep grey matter nuclei and it seems that the brain can handle that quite well. But if there is even a minor amount of iron in the extracellular space even in the ferrous form – because iron normally is stored in the ferric and the trivalent form in ferritin – but if we see even minor amounts in the ferrous form, then it might be detrimental at very low amounts actually.   MSDF Is this a result or a marker of what's going on, or does it really contribute somehow to the disease?   Dr. Hametner This is a very interesting question. We think that iron really colocalizes or is found and accumulated at sites where things are going on with these lesions which accumulate iron in the microglia and macrophages around them. On the other hand, you can detect it very nicely with magnetic resonance imaging today. So we think that on the one hand it does play a role in the disease pathogenesis, and on the other hand we think that we can detect really these sites of iron accumulation, for example, around MS lesions.   MSDF Are you doing this only on fixed patient tissue, or do you have animal models of this; how are you exploring it?   Dr. Hametner We have this fixed material on the MS, and I think it's really important to also characterize the human material in very detail to perform all the necessary analysis to characterize what's going on in the human tissue. But, of course, as you mentioned animal models, it's very important to look at the EAE models. And collaboration partners have done that from McGill University in Montreal, Juan Zarruk and Sam David, and we are collaborating with them. And actually now they have been looking at some iron transporters and we are looking at exactly the same iron transporters now in the MS tissue. And they have found it in the same cell types, these iron transporters, in the EAE model being upregulated in the course of EAE as we see now in the MS tissues actually. So we really look for confirmation also from animal models from our collaboration partners.   MSDF And does this work with various kinds of animal models, or is it restricted to the EAE?   Dr. Hametner This survey has now been performed on the EAE, so it is a mock EAE actually and that they have performed a relapsing-remitting mock EAE in the chronic EAE model, and they have characterized those proteins, but they also do spinal cord injury models and they have performed a very interesting experiment on iron-loading in macrophages in the course of spinal cord injury where the iron gets into the macrophages possibly from a hemoglobin source from erythrocytes in the traumatic lesional tissue. And we think that regardless of the source of iron, it has these detrimental effects in the macrophages and triggers them to have a pre-inflammatory – or so to speak, M1 state – and are detrimental to the surrounding tissue.   MSDF This is macrophages or also microglia?   Dr. Hametner So in the spinal cord injury model, it was mainly macrophages. In the acute phases of the EAE at the peak of the disease, it was also mainly macrophages, but later they also found iron in the animal model within microglia, as we do also in MS. We have these early lesions where there are a bunch of macrophages in these classical active lesions, and these are mainly macrophages, and if they are iron-loaded, it is in the macrophages. But for the later lesions for these chronic active lesions which have this iron ring around the lesion, we find it also within macrophages but also microglia.   MSDF So does this change the oxidative environment inside the macrophage?   Dr. Hametner That's a good question. We think that it does change something with the macrophages because they seem to die. So we have these dying macrophages in the EAE model, as they have observed it, but in the MS we saw this dystrophic microglia at the lesion edge. So these are microglia which are highly iron-loaded probably for some time, and they have these nice processes. And if these processes get those beads and the process fragmentation and these process budding and blips in the processes, we call them senescent or that dystrophic microglia. And we have indications that this is really related to the iron load of this microglia. And then they get diminished towards the inactive centers of the lesion. So we think that at the edge of chronic active or slowly expanding MS lesions, these get iron-loaded in microglia and they don't handle it quite well, and then they die and get diminished towards the inactive centers.   MSDF So when they die, do they release this and is it affecting other cells?   Dr. Hametner We believe so. We think more or less that it is necessarily released into the extracellular space if an iron-loaded cells just dies by necrosis, or apoptosis, or something in between. So it is just released into the extracellular space. It has to be taken up by other cells; for example, other microglia, or other macrophages, or even astrocytes; it seems that it is really liberated. But, of course, it is hard to say whether iron within a specific microglia has been acquired by some other microglia which has died, or by some oligodendrocyte which has died, or even another source. But the fact is although we are sure that they have really accumulated lots of iron, and given actually the concentration of iron in these microglia and the surrounding tissue, we do think that there must be other sources than only oligodendrocytes by which iron gets into these microglia.   MSDF Where do you go from here? What do you see the steps in the research?   Dr. Hametner  I think it is necessary to characterize these rings around lesions which have these iron-loaded microglia and macrophages, to characterize at which disease phases these rings occur, and, of course, this is very interesting because you can use it in vivo. Because one of the things we are really sure is that we can image iron within microglia at the lesion edge of those lesions very nicely at 7 Tesla of magnetic resonance imaging; we are very sure that this is iron then within microglia and macrophages. And if we can relate pathologically the disease mechanisms or the degenerative actions going on in these lesions to the presence of iron, we then can also relate our in vivo findings from MRI with the things which are going on there, like neural degeneration and demyelination, for example.   MSDF Do you find that the iron-sensitive MRI imaging correlates with duration of the disease or stage or clinical condition?   Dr. Hametner Yes, we think so from our pathological material. So we think that in the progressive stage of MS, there are these lesions which are the slowly-expanding lesions, and they have these chronic activity, chronic demyelinating activity at the lesion edge. And we think it's a typical feature of progressive MS. It remains to be determined whether this also holds true in vivo. If you make an MRI, an iron-sensitive MRI, and you look for iron rings around MS lesions, for example, by susceptibility-weighted imaging or by quantitative susceptibility mapping or even Ultrastar imaging, if you look at these iron rings around lesions, it remains to be determined at which disease phase is, because in the pathological material we have more of the chronic cases and we have very few relapsing-remitting. So we cannot say what's really going on in the relapsing-remitting disease because we don't have this material pathologically.   MSDF Right, you would have to find people in various stages who probably died from something else; they're not going to be advanced MS patients at that point. Is there some relationship of your findings to the idea of oxidative stress?   Dr. Hametner Yes, we have these overactivity for malondialdehyde or E06, which is this antibody against oxidized phospholipids, and we have found actually by working performed partly in this lab that there is a higher activity for oxidative stress of various glial cells in the lesions. But as for the microglial degeneration, we did not see so many microglia being positive for these markers. So the microglia, they seem to die, but we only have these morphological features of dystrophic or senescent microglia actually from the pathological side. On adjacent side, if you stain for iron and you stain for oxidized phospholipids, you see partly that there is a 1:1 colocalization. But we don’t see these always actually.   I think what's really clear is that there is lots of oxidative stress in MS lesions, but even in early MS lesions which on iron stainings don't have so much iron, because on these early lesions we actually see predominant iron loss. If you have a very highly active MS lesion in the early stages, you see iron loss, and you will see also oxidative damage there. So there is also other factors leading to oxidative stress, like NADPH oxidase, for example, the p22phox, the functional subunit of NADPH oxidase, which we have shown in this lab that it is upregulated on macrophages and microglia, but also in the absence of iron.   MSDF What tips the balance between loss and iron accumulation?   Dr. Hametner That's an interesting question, actually a complicated one. You're right, we see on the one hand iron loss, and we see iron accumulation. So in the early stages, we see iron loss around MS lesions, in the MS lesions, because oligodendrocytes try to get rid of their intracellular iron possibly to prevent the iron efflux or iron liberation, which is uncontrolled if there is demyelination and oligodendrocyte degeneration actually. So we think that inflammation in the early phases of the disease leads to this efflux, which we think also involves not only oligodendrocytes, but also astrocytes. So we now think actually that oligodendrocytes probably efflux the iron towards astrocytes, and those astrocytes then might efflux it towards the periphery even. So I think inflammation is an obvious candidate to trigger this upregulation of iron efflux mechanisms.   I think what drives the iron accumulation within the microglia at the lesion edges is a different story. We think that these are two unrelated processes. On the one hand you have these iron loss mechanisms, the iron efflux mechanisms from the oligos leading to iron loss in early MS lesions, and this seems to be a protective phenomenon; this is, so to speak, a protective reaction of the glial cells against oxidative stress. But in later lesions, in chronic active lesions with this iron accumulation within microglia and macrophages, and we don't think that they are really correlated. So we think these are two distinct processes going on in MS, probably even in two distinct phases of the disease.   MSDF Is there anything interesting to add?   Dr. Hametner I think the really crucial question is now to find out about the source of iron for microglia and macrophages, and even to find out about the source of iron for the oligodendrocytes. We are not so sure whether this is really transferrin-bound iron entering the brain and being loaded in oligodendrocytes, as you find it in control tissue, control brains. And we don't think that this is only this iron from the oligodendrocytes which is then loaded into the microglia and macrophages; we think there are additional sources possibly from the vasculature.   MSDF Very good, thank you.   [transition music]   Thank you for listening to Episode Forty-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]   Host – Dan Keller Hello, and welcome to Episode Forty-Four 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. Monika Bradl, who discusses animal models of neuromyelitis optica, NMO. But first, here are some of the new items on the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 69 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One – on the use of MRI in NMO –included no fewer than 48 co-authors, a veritable Who’s Who of prominent MS researchers. The other editor’s pick, which had “only” 36 co-authors, was a large study providing strong evidence that disease-modifying treatment reduces disability worsening events in clinically isolated syndrome and early MS. . [transition music]   Now to the interview. Dr. Monika Bradl is an associate professor in the center for brain research at the Medical University of Vienna, Austria. I talked to her in her office about her work with animal models of neuromyelitis optica to probe what occurs in the early stages of the disease. She first describes why animal models are important.   Interviewee – Monika Bradl NMO is a very rare disease, and so you have the problem that you get only very little pathological material, and so when you want to know what's going on at the very beginning of the disease you have to use animal models. And so our pioneer work there in the NMO field was to find out whether the antibody that characterizes about 80% of NMO patients, that's an antibody directed against aquaporin-4, water channel astrocytes, is pathogenic or not. And so what we did is that we injected this antibody then in experimental animals. When we had the animals without any additional CNS inflammation going on, they remained completely fine, and that was at that time a bit of a debate because people thought that the antibodies could enter the central nervous system anyhow.   But then it turned out that this failure of the antibody to reach the uninflamed brain had also predecessor in humans. There they had an NMO patient in Japan who was diagnosed with NMO, and when they found that he has pathogenic antibodies, they were first afraid because this patient was blood donor with the Japanese Red Cross, and so at that time then they stored serum samples of all the blood donors for quite some time, and they found out that this person had pathogenic antibodies already for more than 10 years without showing any signs of disease.   And so this was then the human patient correlated to what we found in our NMO animals, and what we then also saw is immediately when we make our CNS inflammation with CNS-specific T cells which break open the blood-brain barrier, then the antibody gets access to the central nervous system, binds to the astrocytes, and then induces two different type of killing procedures. So the astrocytes are then killed with either the help of complement or with the help of a mechanism that's called antibody-dependent cytotoxicity; so both of these mechanisms are then responsible for tissue destruction.   Interviewer – Dan Keller Getting back to the Japan patient, did they also follow the recipients of that person's blood? It seems like this patient did not have that second hit which would allow the antibody to cause problems, but giving it passively to someone who already had the first hit might cause a problem. Did they look at the recipients?   Dr. Bradl I'm sure they did, but there are no records about it to my knowledge. They might have been published in Japanese in some of these Japanese journals, but not in the international journals. But I'm quite sure that there was no immediate transfer of the disease with these antibodies because that would have made headlines. So one can conclude from that that this must have been harmless.   MSDF And what animal models are you using?   Dr. Bradl We are using rat models, but there are other groups that are working in mice. We use Lewis rats and we think they are great because the rat complement works with the human antibodies, so it provides the help. And we have an NMs strain the Lewis rat which is extremely susceptible to all different types of autoimmune diseases, and so therefore we like rats and their CNS is larger and nicer. But people who work with mice, they also have advantages because they can use the entire transgenic zoo of knockouts or gene-mutated animals, and with this they can learn more about the contribution of individual molecules to the disease process.   MSDF Now that you bring up the mice, are some mice more susceptible based on MHC than others; are some resistant?   Dr. Bradl There you have to consider one peculiarity of the mouse system. If you use mice, then you have the wrong complement system. So no matter what kind of inbred strain you use, you have to transfer human complement along with the human antibodies to get an effect, plus people who use the mouse model directly inject complement and antibodies into that brain to circumvent the blood-brain barrier. And when they do that, the MHC type of the particular mouse strain doesn't play a role.   MSDF Is this using only passively transferred antibody, or do you try to raise antibodies by injecting antigen or modifying antigen?   Dr. Bradl Yup. We desperately try to do so, but I have to say that this was not a real success story. So we first tried, as many other people did, to use just convention and normal aquaporin-4 as it is normally produced, or longer fragments of this, but obviously this does not work. And we now know that the antibody recognizes its target only if the aquaporin-4 is correctly folded within the same membrane. And only if this is the case, then there are three extra cellular loops which are available for antibody binding, and these three loops must be properly oriented and strictly optimally aligned in order for the antibody to bind. And this can only be hardly mimicked in the animal model just by immunization.   We then tried also to immunize with membranes of aquaporin-4 transfected cells, and there we got a little of antibody titer, but when we used these antibodies to stain tissue in order to find out whether they are good one, we saw much more staining than we would have liked, and so that means that the membranes are probably contain some antigens which were then, after immunization, targets of antibody responses. So this was so far in our hands a failure. And as far as I know, we are not the only ones that suffer from that. So there is currently, unfortunately, no model which works after immunization with aquaporin-4.   MSDF Where do you go from here?   Dr. Bradl Well, we are currently modifying our animal models to the extent that we study much more the T cell responses, and we also try to modify the B cell site, but this is a bit of a, let's call it easy way modification. Because we learned along the way that when we have a very, very, very good NMO IgG from a patient, we can work with very low antibody titers, and so that gives us a very nice animal model. And we also know that there are some NMO IgGs which make high titers in the patients but which are relatively lousy in animal models. So we learned from this that we just select and search for the best animal IgG for the model to transfer this; that's the B cell side. And on the T cell side, you'll find T cells in NMO lesions, but people had a hard time to get aquaporin-4 specific T cells.   So it was not quite clear whether one needs aquaporin-4 specific T cells at all for the formation of lesions, or whether any other activated T cell that recognizes different proteins in the CNS could do the job as well. So over the last few months, we now were really able to produce really highly pathogenic aquaporin-4 specific T cells which do the job and which guide lesions to sites where they are also seen in NMO patients. And so with this we were now able to really advance our model much, much more than we had done before.   MSDF So these T cells you've generated, and these are directly cytotoxic?   Dr. Bradl We are not dealing with CD8-positive or cytotoxic T cells, we are dealing with helper T cells. And these helper T cells, we know that they exist because the pathogenic antibodies of the patients have a phenotype that needs T cell help in their formation. But it was all the time unclear whether the T cells only help in antibody formation, or whether they also help in localizing lesions to the correct places. And now we have really for the first time the impression that we have a cell line that does exactly this.   MSDF How do you translate what you're finding out in the animal models to the clinical situation? Is it developed enough now that you can make correlates?   Dr. Bradl Well, that's a good point. I mean, when you look, for example, at our T cell work, then we observed in our animals that there are a large number of epitopes available for antigen recognition by T cells in the rat. And then it turned out that people observed the same thing in mice, and now we know it's also the same thing in humans. And then when you have so many different epitopes or so many different parts of a protein that can be recognized by the immune system, then you have to figure out whether all of them could give rise to pathogenic T cells or not.   And in the Lewis rat, for example, one knows that on myelin basic protein, there are two adjacent peptides which can induce very nice T cell responses, but only one T cell response is pathogenic and the other harmless. And so we initially were facing the same problem with our Lewis rats and the many different epitopes on aquaporin-4, and there we found out that in principle we can also rise T cell responses against many of these epitopes, but we have to use an enormous amount of T cells to get lesions in the CNS.   But with our new T cell line, now we know that we only have to use very few cells to get the lesion, so they are the dominant pathogenic T cells. And it's quite nice that in NMO patients with a very peculiar MHC phenotype – that's an MHC phenotype that's mostly seen Brazilian NMO patients – they recognize dominantly an epitope that's very close to ours, and they termed this also immunodominant epitope. And it could be that it's pathogenic as well, but there is not yet any proof for that in humans.   MSDF Looking at aquaporin-4 as a target in NMO, do these cells just use it as a target to destroy the cell that it's on, or does it result in a pathologic process by inhibiting the action of the channel?   Dr. Bradl There are reports about knockout animals where there is no aquaporin-4 available, also on astrocytes in the CNS. And these animals are apparently healthy under normal conditions, but they show a disease phenotype under conditions where there is tissue swelling going on; for example, under ischemia, and so they cannot cope with that properly. So that means the complete absence of this channel is also bad. Then there are currently two different groups of thinking in the scientific community. There are reports that antibodies can bind to aquaporin-4 and inhibit water flow through this channel, but there are other groups that could not reproduce it. And at the moment it could just be a matter of different antibody preparations or different test systems or different species, so this issue is not 100% solved yet.   MSDF Anything we've missed or interesting to add on the topic?   Dr. Bradl I think the only thing one can say is that since NMO is such an extremely rare disease and since this makes it necessary that people all over the world cooperate with each other, that leads to an enormously research-friendly atmosphere and an enormous willingness of the people to cooperate with each other, and so on all different types of subjects.   MSDF How many patients are there?   Dr. Bradl Well, when you look here in Austria, we have about 8 million inhabitants; there are 8,000 MS patients and approximately 80 NMO patients. And this frequency is more or less encountered throughout the world; it's a very rare disease.   MSDF Very good, thank you.   [transition music]   Thank you for listening to Episode Forty-four 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 Forty-Two 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. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer’s disease, in an animal model of MS.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic’s disease. The conclusion of the meta-analysis is that there’s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.   Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.   Interviewer – Dan Keller Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what’s commonly viewed as a destructive molecule. How did you come upon this?   Interviewee – Lawrence Steinman We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis – EAE. And when she put in these long peptides from an infamous protein named amyloid beta – A-beta – she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they’ll have no effect and then we’ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, “Well, I gave the A-beta peptides and the animals are all better, they’re walking around.” And I first reacted, no, you must have confused the cages, let’s do it again. And when we did it again there was the same result, so then we were off to the races.   There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let’s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it’s doing. But, again, my bias, based on the dominant theory in Alzheimer’s disease is that amyloid was going to cause harm in MS as well as Alzheimer’s.   MSDF In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?   Dr. Steinman Actually, it does not get to the brain. We’ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we’re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they’re sort of tilting the balance to enhance spread if it’s going to occur, but we don’t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.   MSDF So if you’re injecting them peripherally, do you think that there is some direct effect, or do you think they’re acting through lymphocytes or other circulating cells?   Dr. Steinman Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they’re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they’re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.   So what they’re doing when we put them into the circulation is they’re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we’ve heard about in reference to Alzheimer’s, we’ve heard the most about apolipoprotein E. So these amyloid molecules, when they’re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.   There’s another set of mechanisms that we’re learning about that we’re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It’s doing another thing that we’re on the verge of publishing, but I’ll sort of give the headline without too many details; it’s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.   MSDF And you have done adoptive transfer of some of these lymphocytes and find similar effects?   Dr. Steinman Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what’s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 – Th1 – then the type 1 interferon is beneficial. So we’ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.   I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that’s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they’re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there’s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.   Now what does this all mean for the Alzheimer’s hypothesis? And we’re doing an audio interview, so I’m sort of smiling wryly. I don’t want to get into that because we haven’t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven’t done that. And we’ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we’ve studied, we see benefit.   MSDF But as a further proof of concept of what you have found in the protective effect of amyloid, you’ve looked at amyloid precursor protein knockout mice. Is that right?   Dr. Steinman Yes. Well, that’s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who’s actually one of the leaders in the field of Alzheimer’s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.   We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there’s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it’s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.   So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer’s, whether Alzheimer’s is an example of neuroinflammation, I leave it to people in that field because I really don’t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I’m talking about, not only from my own lab but from other investigators all over the world.   One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer’s, but I’m not going to be the one that takes on that massive scientific opinion, we’ll just have to see how it works out. I hope everyone’s been right over all these years because we certainly need some answers in that field. And if they are right, then we’ll have to integrate the kinds of things that we’re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer’s when it’s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer’s, then it will be easier to reconcile these different outcomes. But I think we’ll have to be patient; science doesn’t move as fast as some of us would like to have it move.   MSDF What was the time course of seeing a result by injecting the amyloid in your EAE models?   Dr. Steinman It’s very fast. When you inject the amyloid, it’s within 48 hours. If you stop giving the amyloid – we like to give it every day – if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It’s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that’s very interesting.   MSDF The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?   Dr. Steinman So far, we haven’t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you’ll allow for remyelination if there’s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.   MSDF Are you planning any early human trials?   Dr. Steinman Ha! I chuckle because this is a tough one to bring into the clinic. I’ve been funded by people who first scolded me for saying don’t take this too fast into the clinic, because I like to translate results. In this one, we’ll have to be more cautious than we might for other types of therapies.   MSDF Is there anything important to add?   Dr. Steinman I thought the questions were very comprehensive. And as you can see from where our matters stand now, there’s a lot of positive leads to pursue. And I think we’ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I’m working with, but we’ll get there. Thank you.   MSDF Thank you.   [transition music]   Thank you for listening to Episode Forty-two 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]   Host – Dan Keller Hello, and welcome to Episode Forty 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 Raj Kapoor who discusses a clinical trial of the epilepsy drug, phenytoin, for MS. But first, a few updates on the latest developments at MSDF.   We posted an essay by Dr. Katie Lidster of the National Centre for the Replacement, Refinement, & Reduction of Animals in Research, a U.K.-based scientific organization. In her essay, she points out that Dr. Kapoor’s phenytoin study was made possible by the prior development of a refined mouse model of MS that is more humane than experimental autoimmune encephalomyelitis, which results in paralysis. To find Dr. Lidster’s article, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of April, we added 9 new trials, we updated information on 28 trials, and we've added 42 other pieces of information.  The drugs with important additions and changes are alemtuzumab; BAF312; BIIB033, which is also called anti-LINGO-1; daclizumab; dalfampridine; dimethyl fumarate; fingolimod; glatiramer acetate; interferon beta-1a; interferon beta-1b; laquinimod; mitoxantrone; natalizumab; phenytoin; rituximab; RPC1063; and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 42 such articles were published last week. We selected two of them as Editors’ Picks. One is a review of the role of microRNA in MS. The other is an analysis of the cost of MS drugs in the U.S. This study reports several startling facts. For example, first-generation MS drugs, which cost $8000 to $11,000 annually when they were first released, now cost $60,000 a year. And disease-modifying therapies cost two to three times more in the in the US than in comparable countries. This study ties in nicely with our interview with Dr. Kapoor. Phenytoin has been off patent for many years and is dirt cheap. Good news for MS patients? Maybe not. Paradoxically, phenytoin’s low cost may mean that it will never be fully developed for use in MS. To see our curated list of recently published papers, go to msdiscovery.org and click on Papers.   [transition music]   Now to the interview. Dr. Raj Kapoor is a neurologist at the National Hospital for Neurology and Neurosurgery in London, England.   Interviewer – Robert Finn Hello, this is Bob Finn. I'm at the American Academy of Neurology meeting Washington, D.C., and I'm talking with Dr. Ray Kapoor, who's presenting a very interesting study on a trial of phenytoin – also called Dilantin – in optic neuritis. Dr. Kapoor, welcome. So my first question is why phenytoin and why optic neuritis?   Interviewee – Raj Kapoor So phenytoin we use because it works as a sodium channel blocker, and this is based on years of experience and validation in animal models over the years about how neuroprotection could be achieved in MS. And it turns out that sodium channels are quite important for neurodegeneration in the setting of inflammation. And work in London that we've done, work in Yale has validated animal models that say that if you block sodium channels you can achieve neuroprotection. So why phenytoin? Well that comes down to why optic neuritis? We wanted to test sodium channel blockade in a relapse. And optic neuritis has a lot of advantages because you can study the visual system in so many ways. So why phenytoin? Because we think there's a window of opportunity, and a relapse degeneration occurs pretty rapidly. You need to treat quickly to switch off the mechanisms of neurodegeneration. And phenytoin has the advantage that we can load it very quickly and achieve therapeutic levels. So we have here a model of neuroinflammation and neurodegeneration, which we can study using multiple techniques. And we have a drug that we can load and inhibit those mechanisms quickly.   MSDF I find it fascinating that optic neuritis, which is one of the many symptoms of multiple sclerosis, can be used as a model for multiple sclerosis itself.   Dr. Kapoor The important thing there is it's part of the model. And the key is that we have – in MS – two processes going on. We have inflammation flaring up and leading to relapses like optic neuritis; and then, there is perhaps an allied or even a second process going on, which is the slow grumbling degeneration that leads to progression of disability. Now, we've studied both, but what we're focusing on in this study is that acute process that leads to relapses, you know, attacks which occur from time to time. I mean they're quite important in themselves because they don't always recover. We know that with every attack – even if there's apparent recovery – there is underlying damage to the nervous system. So to protect the nerves in any case is self-serving; it's a good idea. But what we are hoping is that this may even be a key to preventing progression, and that would really be a worthwhile target.   MSDF So you say you chose phenytoin because of its effects as a sodium blocker. What's the connection between sodium and neurodegeneration?   Dr. Kapoor What we found many years ago was that in areas of inflammation there can be nerve damage. And the inflammation drives nerve damage through a number of pathways, but one of them is that it actually indirect leads to sodium accumulation inside the nerve fiber, the axons. This has been well worked out in ischemia, as well. So sodium enters axons; it can't leave through the normal sodium pump because they're metabolically inhibited by the inflammation itself. And the sodium exchanges with calcium. So there's a sodium/calcium exchange in the membrane of nerve cells, and if you load them with sodium then sodium has to get out and gets out by driving the influx of calcium, and that's dangerous; that kills axons. So the whole process can be inhibited by inhibiting sodium entry. Now there's another thing that's very important, which is in acute inflammation one of the things that drives it is microglia, activated microglia release chemicals such as nitric oxide, which in themselves drive the whole inflammatory damaging cascade. But it turns out – and this is work from Yale – that actually the microglia themselves have sodium channels, and that their functioning can be inhibited by inhibiting those same channel. So what phenytoin is doing is it's actually inhibiting not only the cascade that damages the axons but is actually inhibiting the cells which are driving the inflammation and causing the damage in the first place.   MSDF Now, is there any indication that phenytoin may be working in this way more centrally than the optic nerve?   Dr. Kapoor It's very unlikely because the mechanism that we've testes is really something well characterized as inflammation within the optic nerve. And we are measuring the damage and the effects of treatment by actually imaging the retina looking at retrograde degeneration from the optic nerve lesion. So I think it's very unlikely given the timescale – you know, we're treating within a couple of weeks of onset, we're having a readout within six months – that it's doing anything other than what we're asking of it, which is a readout of what's going on in the optic nerve and retina.   MSDF If I understand you correctly, even if this is working exactly the way you want it to be, it's not going to be doing anything for people with central damage. Is that correct?   Dr. Kapoor Well I think the thing to understand here is it may do in MS where damage is happening everywhere. This is really a proof of concept. We've tried our very best to isolate the damaging process and to work out whether the theory works. So yes, there may be more general implications, and we think there probably are. But it's important to note that really what we're doing here is choosing a very clearly defined model to test the hypothesis.   MSDF Now one of the advantages of phenytoin is that it's generic; it's dirt cheap. But is that a liability, as well?   Dr. Kapoor Yeah, this is a very important point. So we're talking here about this whole issue of repurposing drugs. And we think that there may be many different drugs on the shelf which may have a role in treating diseases like MS. Now for us that was an advantage. This is an investigator led study, and it was funded by charitable means from the National MS Society and UK MS Society. So that's an advantage because the drug is really cheap. But of course, in terms of development, the commercial reality is that there's very little money in this. And so to take this further, it makes it harder not to have a drug that makes money.   MSDF So what's the solution to that problem?   Dr. Kapoor We don't know. I mean there are lots of ways that we're taking this forward. I mean you may know that there is a thing called the Progressive MS Alliance, which is an international body of MS societies, which is trying to work its way through questions exactly like this establishing industry relations. And it may be that they're a scope for industry to step in. And governments step in sometimes. I mean in the U.K. we have a trial running at the moment which is using funds from government to do a moderately sized Phase 2/Phase 3 trial of neuroprotection. So I think, actually, this all depends on the results. If the results are good, then we hope that either through industry or through government or, indeed, through charitable means there may be a way through. Just to get back to your question, I think that, you know, repurposing is a problem because clearly the commercial angle is far less prominent.   MSDF Is one possible solution to find a drug that's still under patent?   Dr. Kapoor Indeed, that would be a remarkable thing to do. But of course, a trial in the beginning would then need commercial collaboration. But certainly that's an angle.   MSDF So assuming that your research is confirmed and extended and phenytoin proves to be truly neuroprotective, when in the course of MS is it likely to be useful?   Dr. Kapoor So by definition, phenytoin is going to be useful for relapses. The idea that relapses sometimes leave damage and that a drug like phenytoin or phenytoin itself prevents some of that damage speaks for itself. The real question, though, comes down to whether progressive MS is also driven by similar mechanisms. We did a trial of lamotrigine, which is another sodium channel blocking anticonvulsant, and published the results about five years ago now. And that trial was reportedly negative for its primary outcome, which was brain atrophy; could we reduce the rate of loss of brain volume. I suppose what we've done is to go back to that trial and look at positive signals there because after all the question is do sodium channel blockers prevent progressive MS or prevent progression? And in fact, it turns out that there was some remarkable positive signals in that trial. So I have the knowledge that phenytoin should be useful for relapsing MS. But I also have a hunch that it may be useful for progressive MS, as well.   MSDF Now there's a flipside to the fact that phenytoin is so easily available, and that is that physicians listening to this podcast or to other news reports may consider prescribing it off-label. How would you counsel somebody considering that?   Dr. Kapoor I think it's difficult for somebody to use phenytoin in that way because the way the trial was designed was to treat people in a very narrow window after the onset of a relapse. Now people may say well, you know, the next time I see a patient who has a relapse, you know, can't walk or the vision is affected I will immediately prescribe phenytoin. The difficulty I have there is that this remains a very attractive study but hasn't proved the point. And phenytoin is not without its side effects. You know, I'm always somebody who's evidence led, and so I would counsel against using drugs without even further evidence. This is one Phase 2 study after all. I think the temptation will be there nevertheless.   MSDF And if a physician falls to that temptation, what should he or she look for?   Dr. Kapoor Well again, this is the point. We have shown a concept works. You know, we have shown that phenytoin, by a number of measures, prevents nerve damage. I think the difficulty – and I need to be very clear about this – is that with acute optic neuritis where vision generally recovers we didn't see better recovery with phenytoin. So again, perhaps another answer is that if I treat somebody with a relapse with phenytoin I'm not really sure that I may be protecting nerves, but am I producing a better outcome? So that may be another reason to say let's wait for a better drug or a better trial.   MSDF That's a very good point. So is there anything I haven't asked that I should have asked, or anything you'd like to add?   Dr. Kapoor No, I think that really the way I want to convey the result is that it's a robust result. I mean what I'll be presenting is that on a number of measures the drug worked. I think it worked with a modest amount of success. I see this is opening a door. I don't see this as the final answer to a problem. You know, if you think about it, we've been looking for a long time for a neuroprotective drug in MS and a strategy. And I think this is opening a door, which I think needs to be opened a lot wider.   MSDF Dr. Kapoor, thank you very much.   Dr. Kapoor Thank you.    [transition music]   MSDF Thank you for listening to Episode Forty 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]          

It's NOT Soccer PodcastEpisode Forty Seven - Me, Myself and Avatard 2 Guys! 2 Mics! Too Much Information!In This Episode of IT'S NOT SOCCER podcast, Its Not anything really, Adam and Billy sit down to bring to you the first in a series that will span both The ODDcast PODcast UK and The #NOTlistening blog."Films of your life...." is dedciated to a single person as they tell us the films that have affected them in their life so far.In this Episode Billy is in the spotlight as he discusses his first memories of "The Jungle Book", Loving a Jim Carrey comedy and why Avatar upsets Adam.It's NOT Soccer Podcast is a Comedy Podcast with the mixed ramblings of Hosts Adam @BarkerPODcasts and Billy @Bilo66. Each Episode These 2 Guys sit down with 2 Microphones and give out TOO much Information.It's NOT Soccer!........It's NOT Anything ReallyMake sure you follow us on Twitter @NOTsoccerPodPart of The Barker PODcasts Collection at http://barkerpodcasts.webs.comOn Spreaker: http://www.spreaker.com/user/oddcastpodcast

It's NOT Soccer PodcastEpisode Forty Six - Podcast Grammar2 Guys! 2 Mics! Too Much Information!In This Episode of IT'S NOT SOCCER podcast, Its Not anything really, Adam and Billy discuss Adam's love for the band "London Grammar", Billy brings back a Trailer Breakdown segment only to end in shambles, A discussion descends into mumbling and much more.............A Podcast that wins on the basis of trying.It's NOT Soccer Podcast is a Comedy Podcast with the mixed ramblings of Hosts Adam @BarkerPODcasts and Billy @Bilo66. Each Episode These 2 Guys sit down with 2 Microphones and give out TOO much Information.It's NOT Soccer!........It's NOT Anything ReallyMake sure you follow us on Twitter @NOTsoccerPodPart of The Barker PODcasts Collection at http://barkerpodcasts.webs.comOn Spreaker: http://www.spreaker.com/user/oddcastpodcast

It's NOT Soccer PodcastEpisode Forty Five - Worst Dating Advice EVER2 Guys! 2 Mics! Too Much Information!In This Episode of IT'S NOT SOCCER podcast, Its Not anything really, Adam and Billy return from the break. Back on the mics the two sit down and discuss dating! Billy gives his advice to those looking for love, in a podcast recorded over Valentines night.WARNING: The advice in this podcast MUST NOT be taken seriously, else you will end up alone.It's NOT Soccer Podcast is a Comedy Podcast with the mixed ramblings of Hosts Adam @BarkerPODcasts and Billy @Bilo66. Each Episode These 2 Guys sit down with 2 Microphones and give out TOO much Information.It's NOT Soccer!........It's NOT Anything ReallyMake sure you follow us on Twitter @NOTsoccerPodPart of The Barker PODcasts Collection at http://barkerpodcasts.webs.comOn Spreaker: http://www.spreaker.com/user/oddcastpodcast

It's NOT Soccer PodcastEpisode Forty One DOOMBAR! Enough Said!  2 Guys! 2 Mics! Too Much Information!In This Episode of IT'S NOT SOCCER podcast, Its Not anything really, Adam and Billy sit down and discuss Being born ready, selling DOOMBAR and Something about a pair of football boots. Plus much much more.It's NOT Soccer Podcast is a Comedy Podcast with the mixed ramblings of Hosts Adam @BarkerPODcasts and Billy @Bilo66. Each Episode The two sit down and discuss everything worth talking about in the world and much much more. Ranging from English Soccer to International Sports to Random Entertaining news and the Odd revelation from Billy.It's a Sports/Comedy Podcast........Kind Of!Make sure you follow us on Twitter @NOTsoccerPodListen in and enjoy The Show about Sports and More.

Episode Forty-nine - Revenge and murder go hand in hand in "Red Hood" and "Speaking is Easy, Murder is Hard". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-eight - Which is more random, a grim reaper that cares about his clients' opinions or the advertisements on your television? Featuring "Customer Satisfaction" and "These Commercial Messages". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-seven - Not everyone is who they seem. But when you find out who people are on the inside, sometimes you were better off not knowing! Featuring "Massively Multiple Primate Theorem" and "Late Library". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Erin Red is thrilled to welcome hardcore animal activist Simone Reyes to Red Radio in Episode Forty!  Longtime vegan, blogger, reality television star and personal assistant to Super Vegan (and Erin Red's idol) Russell Simmons, Simone lays it on thick while discussing some very powerful topics.  From her humble beginnings running around New York City with the Beastie Boys to her very public demonstrations for PETA, listen in on what makes this brave activist tick and refuel your vegan engines!  Plus, Erin Red weighs in on veganism as it relates to yoga - can you be an Omni Yogi? (Hell naw!)  Please consider supporting Red Radio by visiting erinred.com and clicking the DONATE button, and subscribe to Red Radio on iTunes today!  If you love what you hear, leave a glowing review, or drop Erin Red a line at erinredradio@gmail.com.  You can also read her blog at erinred.tumblr.com, and find her on Facebook and Twitter @erinred.

Episode Forty-six - All is not what it seems as secrets are revealed! Featuring "The Guardian of the Ram" and "San Diego"! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-five - Sonny discovers what it is to be a "Sample" and Lauren relives her "Rebellion"! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-four - The survival of the human race hangs in the balance of a "Vocabulary Test" and Alex finds direction "In the Sun". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-three - Law and justice wrestle as bullets fly! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-two - Humans and otherworldly forces clash as desire exacts its price! Featuring "Lucky You" and "You Gave Me Nothing". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Forty-one - An accountant and a barber explore evil as the hunt heightens at the school! Featuring "The Burrower" and "Barbershop Trio". --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Good day to you:Episode FortyIt's a tabloid special this week, as iszi pulls a rare entrant out of the bag, and Simon takes a long look in the mirror. We're now an officially "awesome" podcast, according to those folk over at the Skeptics' Guide To The Universe, and they only deal in the truth. So thanks everyone for your continued support.