Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

100 episodes

The Multiple Sclerosis Discovery Forum (MSDF) is an online resource that aims to accelerate progress toward cures for multiple sclerosis and related disorders by sparking new ideas and catalyzing unforeseen connections. The site focuses attention on what is known and not yet known about the causes of these conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we will open new routes toward significant clinical advances. The podcast will include the latest in MS research news as well as one-on-one interviews with prominent MS researchers and clinicians. While the podcast is intended mainly for other researchers and clinicians, we welcome people with MS, their caregivers, and anyone else with an interest in multiple sclerosis and related disorders.

Podcasts

Interview with Richard Cohen

Published: April 25, 2018, 8:54 p.m.
Duration: 33 minutes 39 seconds

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Interview with Marc Stecker, the Wheelchair Kamikaze

Published: Jan. 25, 2018, 7:37 p.m.
Duration: 32 minutes 47 seconds

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Multiple Sclerosis Discovery -- Episode 98 with Dr. David Baker

Published: Sept. 2, 2016, 8:51 p.m.
Duration: 15 minutes 40 seconds

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Multiple Sclerosis Discovery -- Episode 97 with Dr. David Baker

Published: Sept. 2, 2016, 8:12 p.m.
Duration: 14 minutes 53 seconds

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Multiple Sclerosis Discovery -- Episode 96 with Drs. Bibiana Bielekova and Mika Komori

Published: Aug. 26, 2016, 10:45 p.m.
Duration: 19 minutes 14 seconds

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Multiple Sclerosis Discovery -- Episode 95 with Dr. Michael Levy

Published: Aug. 19, 2016, 10:35 p.m.
Duration: 11 minutes 3 seconds

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Multiple Sclerosis Discovery -- Episode 94 with Dr. Oscar Fernandez

Published: Aug. 5, 2016, 7:59 p.m.
Duration: 10 minutes 29 seconds

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Multiple Sclerosis Discovery -- Episode 93 with Dr. Lilyana Amezcua

Published: Aug. 5, 2016, 6:19 p.m.
Duration: 11 minutes 35 seconds

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Multiple Sclerosis Discovery -- Episode 92 with Dr. Shiv Saidha

Published: Aug. 4, 2016, 8:49 p.m.
Duration: 21 minutes 2 seconds

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Multiple Sclerosis Discovery -- Episode 91 with Dr. Jorge Nogales-Gaete

Published: July 21, 2016, 10:03 p.m.
Duration: 13 minutes 20 seconds

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Multiple Sclerosis Discovery -- Episode 90 with Dr. Daniel Hartung

Published: July 21, 2016, 9:06 p.m.
Duration: 20 minutes 29 seconds

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Multiple Sclerosis Discovery -- Episode 89 with Dr. Charity Evans

Published: July 6, 2016, 6:01 p.m.
Duration: 8 minutes 53 seconds

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Multiple Sclerosis Discovery -- Episode 88 with Dr. John Hart

Published: June 16, 2016, 4:08 p.m.
Duration: 21 minutes 42 seconds

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Multiple Sclerosis Discovery -- Episode 87 with Dr. Ellen Mowry

Published: June 11, 2016, 4:15 p.m.
Duration: 7 minutes 6 seconds

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Multiple Sclerosis Discovery -- Episode 86 with Dr. Pavan Bhargava

Published: May 27, 2016, 1:18 p.m.
Duration: 14 minutes 1 second

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Multiple Sclerosis Discovery -- Episode 85 with Dr. Eva Havrdová

Published: May 20, 2016, 5 p.m.
Duration: 10 minutes 29 seconds

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Multiple Sclerosis Discovery -- Episode 84 with Dr. Ilya Kister

Published: May 20, 2016, 4:58 p.m.
Duration: 15 minutes 45 seconds

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Multiple Sclerosis Discovery -- Episode 83 with Dr. Jerry Wolinsky

Published: May 17, 2016, 5:09 p.m.
Duration: 18 minutes 9 seconds

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Multiple Sclerosis Discovery -- Episode 82 with Dr. Adam Kaplin

Published: May 17, 2016, 5:07 p.m.
Duration: 21 minutes 6 seconds

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Multiple Sclerosis Discovery -- Episode 81 with Dr. Kaarina Kowalec

Published: May 11, 2016, 1:15 p.m.
Duration: 12 minutes 9 seconds

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Multiple Sclerosis Discovery -- Episode 80 with Dr. Kaarina Kowalec

Published: May 11, 2016, 1:14 p.m.
Duration: 12 minutes 38 seconds

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Multiple Sclerosis Discovery -- Episode 79 with Dr. Nancy Monson

Published: May 11, 2016, 1:13 p.m.
Duration: 16 minutes 14 seconds

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Multiple Sclerosis Discovery -- Episode 78 with Dr. Dessa Sadovnick

Published: May 11, 2016, 1:11 p.m.
Duration: 20 minutes 39 seconds

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Multiple Sclerosis Discovery -- Episode 77 with Dr. Annette Langer-Gould

Published: May 8, 2016, 8:02 p.m.
Duration: 19 minutes 38 seconds

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Multiple Sclerosis Discovery -- Episode 76 with Dr. Dessa Sadovnick

Published: May 2, 2016, 6:48 p.m.
Duration: 16 minutes 30 seconds

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Multiple Sclerosis Discovery -- Episode 75 with Dr. Elaine Kingwell

Published: April 29, 2016, 12:28 p.m.
Duration: 12 minutes 37 seconds

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Multiple Sclerosis Discovery -- Episode 74 with Dr. Markus Reindl

Published: April 25, 2016, 10:01 p.m.
Duration: 13 minutes 35 seconds

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Multiple Sclerosis Discovery -- Episode 73 with Dr. Donna Osterhout

Published: April 13, 2016, 7:38 p.m.
Duration: 19 minutes 28 seconds

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Multiple Sclerosis Discovery -- Episode 72 with Mr. Nathaniel Lizak

Published: March 25, 2016, 7:26 p.m.
Duration: 16 minutes 36 seconds

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Multiple Sclerosis Discovery Forum -- Episode 71 with Brian Weinshenker

Published: March 18, 2016, 5:32 p.m.
Duration: 20 minutes 51 seconds

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Multiple Sclerosis Discovery -- Episode 70 with Dr. Brian Weinshenker

Published: March 8, 2016, 5:31 p.m.
Duration: 18 minutes 20 seconds

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Multiple Sclerosis Discovery -- Episode 69 with Dr. Alessandra Solari

Published: Feb. 29, 2016, 4:35 p.m.
Duration: 16 minutes 49 seconds

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Multiple Sclerosis Discovery -- Episode 68 with Dr. Philip De Jager

Published: Feb. 10, 2016, 5:40 p.m.
Duration: 18 minutes 16 seconds

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Multiple Sclerosis Discovery -- Episode 67 with Neda Razaz

Published: Jan. 26, 2016, 11:58 p.m.
Duration: 11 minutes 41 seconds

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Multiple Sclerosis Discovery -- Episode 66 with Dr. Jeremy Hobart

Published: Jan. 19, 2016, 8:45 p.m.
Duration: 19 minutes 22 seconds

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Multiple Sclerosis Discovery -- Episode 65 with Dr. Gisela Kobelt

Published: Jan. 13, 2016, 10:52 p.m.
Duration: 18 minutes 35 seconds

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Multiple Sclerosis Discovery -- Episode 64 with Dr. Helen Tremlett

Published: Jan. 5, 2016, 9:35 p.m.
Duration: 13 minutes 33 seconds

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Multiple Sclerosis Discovery -- Episode 63 with Dr. Helen Tremlett

Published: Dec. 28, 2015, 1:13 a.m.
Duration: 15 minutes 18 seconds

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Multiple Sclerosis Discovery -- Episode 62 with Dr. Ellen Mowry

Published: Dec. 21, 2015, 2:26 p.m.
Duration: 15 minutes 49 seconds

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Multiple Sclerosis Discovery -- Episode 61 with Dr. Yanming Wang

Published: Dec. 10, 2015, 4:16 p.m.
Duration: 11 minutes 59 seconds

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Multiple Sclerosis Discovery -- Episode 60 with Dr. Timothy Vollmer

Published: Nov. 16, 2015, 2:50 p.m.
Duration: 14 minutes 32 seconds

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Multiple Sclerosis Discovery -- Episode 59 with Dr. Helmut Butzkueven

Published: Nov. 4, 2015, 11:12 a.m.
Duration: 16 minutes 14 seconds

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Multiple Sclerosis Discovery -- Episode 58 with Dr. Gavin Giovannoni

Published: Oct. 27, 2015, 7:52 p.m.
Duration: 17 minutes 23 seconds

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Multiple Sclerosis Discovery -- Episode 57 with Dr. Timothy Vollmer

Published: Oct. 20, 2015, 5:46 p.m.
Duration: 13 minutes 38 seconds

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Multiple Sclerosis Discovery -- Episode 56 with Dr. Gavin Giovannoni

Published: Oct. 16, 2015, 7:32 p.m.
Duration: 17 minutes 39 seconds

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Multiple Sclerosis Discovery -- Episode 55 with Dr. Michael Levy

Published: Oct. 5, 2015, 6:54 p.m.
Duration: 16 minutes 22 seconds

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Multiple Sclerosis Discovery -- Episode 54 with Dr. Jonathan Kipnis

Published: Sept. 29, 2015, 9:56 p.m.
Duration: 14 minutes 48 seconds

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Multiple Sclerosis Discovery -- Episode 53 with Dr. Jonathan Kipnis

Published: Sept. 11, 2015, 6:24 p.m.
Duration: 14 minutes 36 seconds

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Multiple Sclerosis Discovery -- Episode 52 with Dr. David Tabby

Published: Sept. 2, 2015, 9:11 p.m.
Duration: 14 minutes 8 seconds

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Multiple Sclerosis Discovery -- Episode 51 with Dr. Luke Lairson

Published: Aug. 21, 2015, 6:36 p.m.
Duration: 16 minutes 31 seconds

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Multiple Sclerosis Discovery -- Episode 50 with Dr. David Tabby

Published: July 31, 2015, 10:11 p.m.
Duration: 14 minutes 48 seconds

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Multiple Sclerosis Discovery -- Episode 49 with Dr. Hugh Rosen

Published: July 21, 2015, 5:36 p.m.
Duration: 22 minutes 38 seconds

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Multiple Sclerosis Discovery -- Episode 48 with Dr. Bruce Cree

Published: July 13, 2015, 6:38 p.m.
Duration: 25 minutes 18 seconds

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Multiple Sclerosis Discovery -- Episode 47 with Dr. Hans Lassmann (Part 2)

Published: July 2, 2015, 7:06 p.m.
Duration: 15 minutes 36 seconds

 

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Multiple Sclerosis Discovery -- Episode 46 with Dr. Hans Lassmann (Part 1)

Published: June 24, 2015, 5:43 p.m.
Duration: 21 minutes 53 seconds

 

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Multiple Sclerosis Discovery -- Episode 45 with Dr. Simon Hametner

Published: June 12, 2015, 12:12 a.m.
Duration: 19 minutes 9 seconds

 

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Multiple Sclerosis Discovery -- Episode 44 with Dr. Monika Bradl

Published: June 4, 2015, 9:11 p.m.
Duration: 17 minutes 23 seconds

 

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Multiple Sclerosis Discovery -- Episode 43 with Dr. May Han

Published: May 27, 2015, 6:28 p.m.
Duration: 18 minutes 12 seconds

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Multiple Sclerosis Discovery -- Episode 42 with Dr. Lawrence Steinman

Published: May 19, 2015, 5:27 p.m.
Duration: 19 minutes 18 seconds

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Multiple Sclerosis Discovery -- Episode 41 with Dr. Diego Cadavid

Published: May 12, 2015, 11:46 p.m.
Duration: 14 minutes 35 seconds

 

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Multiple Sclerosis Discovery -- Episode 40 with Dr. Raj Kapoor

Published: May 4, 2015, 9:49 p.m.
Duration: 16 minutes 26 seconds

 

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Multiple Sclerosis Discovery -- Episode 39 with Dr. Joseph Berger (part 2)

Published: April 29, 2015, 11:13 p.m.
Duration: 19 minutes 29 seconds

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Multiple Sclerosis Discovery -- Episode 38 with Dr. Joseph Berger

Published: April 21, 2015, 9:53 p.m.
Duration: 23 minutes

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Multiple Sclerosis Discovery -- Episode 37 with Dr. Jeanne Loring

Published: April 14, 2015, 12:22 a.m.
Duration: 20 minutes 58 seconds

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Multiple Sclerosis Discovery -- Episode 36 with Dr. Jenny Ting

Published: April 8, 2015, 5:20 p.m.
Duration: 17 minutes 6 seconds

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Multiple Sclerosis Discovery -- Episode 35 with Dr. Daniel Reich

Published: March 23, 2015, 6:07 p.m.
Duration: 21 minutes 7 seconds

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Multiple Sclerosis Discovery -- Episode 34 with Dr. Jill Hollenbach

Published: March 10, 2015, 5:30 p.m.
Duration: 14 minutes 9 seconds

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Multiple Sclerosis Discovery -- Episode 33 with Dr. Pierre-Antoine Gourraud

Published: March 2, 2015, 6:30 p.m.
Duration: 11 minutes 54 seconds

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Multiple Sclerosis Discovery -- Episode 32 with Dr. David Holtzman

Published: Feb. 18, 2015, 12:39 a.m.
Duration: 18 minutes

 

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Multiple Sclerosis Discovery -- Episode 31 with Dr. Lloyd Kasper

Published: Feb. 10, 2015, 1:47 a.m.
Duration: 19 minutes 7 seconds

 

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Multiple Sclerosis Discovery -- Episode 30 with Dr. Seema Tiwari-Woodruff

Published: Feb. 3, 2015, 1:15 a.m.
Duration: 19 minutes 49 seconds

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Multiple Sclerosis Discovery -- Episode 29 with Dr. Monica Carson

Published: Jan. 26, 2015, 10:44 p.m.
Duration: 15 minutes 53 seconds

 

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Multiple Sclerosis Discovery -- Episode 28 with more from Dr. Brenda Banwell

Published: Jan. 20, 2015, 7:38 p.m.
Duration: 21 minutes 10 seconds

 

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Multiple Sclerosis Discovery -- Episode 27 with Dr. Brenda Banwell

Published: Jan. 12, 2015, 11:21 p.m.
Duration: 12 minutes 29 seconds

 

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Multiple Sclerosis Discovery -- Episode 26 with Dr. Tim Kennedy

Published: Jan. 6, 2015, 12:56 a.m.
Duration: 18 minutes 22 seconds

 

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Multiple Sclerosis Discovery -- Episode 25 with actor and science afficionado Alan Alda

Published: Dec. 15, 2014, 10:01 p.m.
Duration: 15 minutes 7 seconds

 

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Multiple Sclerosis Discovery -- Episode 24 with Professor Aksel Siva

Published: Dec. 9, 2014, 9:48 p.m.
Duration: 15 minutes 45 seconds

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Multiple Sclerosis Discovery -- Episode 23 with Professor Aksel Siva

Published: Dec. 1, 2014, 8:03 p.m.
Duration: 18 minutes 5 seconds

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Multiple Sclerosis Discovery -- Episode 22 with Dr. Paul Matthews

Published: Nov. 24, 2014, 10:08 p.m.
Duration: 14 minutes 58 seconds

 

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Multiple Sclerosis Discovery -- Episode 21 with Dr. Paul Matthews

Published: Nov. 17, 2014, 10:26 p.m.
Duration: 15 minutes 3 seconds

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Multiple Sclerosis Discovery -- Episode 20 with Dr. Jeffrey Cohen

Published: Nov. 10, 2014, 8:25 p.m.
Duration: 17 minutes 4 seconds

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Multiple Sclerosis Discovery -- Episode 19 with Dr. Samuel Ludwin

Published: Nov. 3, 2014, 8:21 p.m.
Duration: 20 minutes 15 seconds

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Multiple Sclerosis Discovery -- Episode 18 with Dr. Samuel Ludwin

Published: Oct. 27, 2014, 5:40 p.m.
Duration: 17 minutes 46 seconds [intro music]

 

Hello, and welcome to Episode Eighteen 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. Samuel Ludwin about new approaches to remyelinating therapies. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.

 

Speaking of remyelination, we recently published an article in our animal model section about zebrafish and their use in studying MS. Though a fish might not jump to mind as an adequate model for modeling the complexities of a disease like MS, zebrafish are actually very useful for studying myelination. Researchers can engineer the fish to be transparent while also fluorescently tagging myelin, oligodendrocytes, and more. If you’re curious to learn more, go to the “Animal Models” section under “Research Resources” and click on “Zebrafish.”

 

Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”

 

[transition music]

 

Now to the interview. Dr. Samuel Ludwin is a neuropathologist who is currently a visiting scientist at the Montreal Neurological Institute. He met with MSDF to talk about the latest in remyelination therapies.

 

Interviewer—Dan Keller

In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it?

 

Interviewee—Samuel Ludwin

Remyelination is a very interesting process. We know that it occurs in animals. We can well demonstrate its temporal progression. We can demonstrate the conditions under which it occurs. Demonstrating this in the human is very much more complicated because we are always taking snapshots in time in looking at human specimens and we can never be sure whether we are looking at a remyelination of a previously completely demyelinated process or not. So we draw all of our analogies about human remyelination, which we believe is present in multiple sclerosis and other diseases, but we draw these analogies from what we have shown in experimental animals where we have been able to control the process.

 

In animals, first of all, it is very feasible for a variety of reasons. The first is that – many mammalian, especially rodent brains, and marmoset brains which we generally work on – are considered in a way functionally immature which tends to suggest that their brains are much more capable of plasticity and therefore much more able to be repaired. The same process probably does occur in humans but as I said is probably a little bit less certain. We have done a lot of work in multiple sclerosis in demonstrating that the hallmark of remyelination which is a reconstituted sheath, although with different physical characteristics to the original myelin. We can find these sheaths in the human tissue in areas that we think are remyelinating. This brings up the promise that a certain amount of natural remyelination occurs in response to demyelination in disease. There is always the hope that one can use some of the same factors that we have discovered in rodents and other experimental animals to enhance this remyelination and make for a much wider area of functional…both enhancement of function and also protection of the underlying axons.

 

So remyelination is one of the hopes and maybe promises in multiple sclerosis research. Proving it is a little bit more difficult. We have many possible mechanisms for enhancing remyelination. Some of them are considered to be cell-based. By that we mean what is preventing remyelination often is the destruction of the oligodendrocyte and its precursor cells which can develop into myelinating oligodendrocyte. A lack of these cells will obviously result in a deficient remyelination. Secondly, there may be blocks from either the axon which gives the message and the signal for remyelination. Thirdly, there may be physical barriers such as the reaction from other cells in response to the inflammatory insult that are hindering access by these oligodendrocytes to the axon in order to make myelin.

 

There are many possible reasons that we don't have adequate remyelination. For each of these, there are at least some punitive answers as to how we may enhance. There is a lot of interest in cell transplantation, especially with mesenchymal stem cells at the moment; which have been shown not only to have immunological benefits of antiinflammatory qualities but also to be able to then differentiate into these oligodendrocyte precursors which will then differentiate into myelinating oligodendrocytes. These may enable the brain to reconstitute its quotient of myelinating cells.

 

There are lots of attempts underway to try and prevent any of the physical barriers of access of these cells to the axon such as from the astrocytic gliosis, but there are also many drugs which have the possibility of enhancing human remyelination. Many of these have been shown to work very well in animal models. We have whole classes of drugs that enhance remyelination. There are steroidal compounds that have been shown to enhance myelination and there have been many that have been shown to either block some of the cytokines that may be hindering or interfering with the progression of oligodendrocyte maturation. Drugs that will block some of these cytokines will allow this maturation of proliferation of these cells to continue, and therefore lead to maturation. It is true to say that apart from some of the mesenchymal stem cells which have some hope; it has been very difficult to measure remyelination in response to these therapeutic attempts at the moment in humans. Certainly in rodents we have been able to do it and there are certain clinical trials going on based on some of these animal experiments. There is a trial which the NIH is doing in conjunction with the Myelin Repair Foundation over a compound 008 which has been shown to be very beneficial in certain demyelinating models and enhancing remyelination. There are certain growth factors that have been given in animals such as hepatic growth factor that have been shown to enhance the number of oligodendrocyte precursors and their development into oligodendrocytes. These all give promise for what is possible in humans but have not yet been taken to that level yet.

 

MSDF

It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work?

 

Dr. Ludwin

What is very interesting is that there is a whole gamut of drugs that are being investigated ab intio arising out of experiments that have been shown to have an influence on the inflammatory aspect of autoimmune disease. Many of the cytokines induced by the autoimmune diseases have multiple effects on the oligodendrocyte proliferation, maturation and then access to the axon. So drugs that will inhibit this cascade of cytokines in autoimmunity will also remove some of these inhibitors and allow for enhanced proliferation and maturation and therefore enhanced remyelination. In addition, there are a whole emerging group of drugs that have been found to coincidentally have an affect experimentally on remyelination and many of these drugs have been in the pharmacopeia for other diseases and these are side effects or side discoveries. Some of them have not been used for their initial purpose for a long time and this includes a drug that is currently under clinical trials with the NIH and the Myelin Repair Foundation called MRF-008, the details of which are not public, either in mechanism or in the structure of the drug. There are also classes of drugs such as estrogen and progesterone based drugs which have been introduced because of observable influences of normal estrogen progesterone function on oligodendrocytes and Schwann cells in the periphery in culture and they relate also to hormonal variations in multiple sclerosis and are a natural outcome of some of these observations.

 

MSDF

It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that.

 

Dr. Ludwin

Oh absolutely. I mean when we look at general repair foundations, we are looking at two of them. First of all, there is the whole question of neuroprotection and second of all there is the whole question of regrowth and these in form, are we looking at regrowth of axons, sprouting of axons in multiple sclerosis. There is a large amount of axonal damage which needs to be investigated for protection and such strategies will be very useful in axonal damage and in the hope of producing axonal regeneration.

 

MSDF

Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories?

 

Dr. Ludwin

Some of them may do both but in general the neuroprotective drugs are generally a different class or different kind of drugs. There is a great need to introduce them into stroke, into trauma, the neuroprotective drugs and people are looking at the same strategies that are being used for ischemia and anoxia which are the results of strokes but may also very possibly play a role in the lesions in multiple sclerosis to protect the axons. Some of these are excitotoxic protection agents which the axon is particularly susceptible to both in ischemia and in multiple sclerosis.

 

MSDF

You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate?

 

Dr. Ludwin

No, that is a very good question. In fact, neurotransmitter excitotoxicity has been demonstrated very well in multiple sclerosis, especially in the acute lesions where perhaps most of the axonal injury takes place. We always used to think that it was all a progressive lesion but a huge amount takes place early on in and much of this is in excitotoxic damage. I might add also that in many respects the oligodendrocyte has got many of the same neurotransmitter capacities as does the axon and neuron and the oligodendrocyte itself is susceptible to excitotoxic damage as well. Excitotoxicity is a very important target for neuroprotection and protection of the oligodendrocyte as well.

 

MSDF

On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add?

 

Dr. Ludwin

I think that covers it in general. Of course, what we really are looking for is what the triggers to the acute process are. What we are doing, the autoimmune aspect, is the largest looming figure in the one that is proven most and almost certainly represents the major way that tissue is damaged. But what provokes the autoimmune attack may give us the answer to at least preventing or slowing down the AMS process. The therapy is at the moment largely based around dampening of the autoimmune attack and preventing subsequent damage. Although I should point out that it is not only the loss of myelin that leads to excitotoxic damage in the axon but the inflammatory infiltrate that kills oligodendrocytes and myelin has the same mechanisms that kill the axon as well. We are not just trying to protect, we are trying to prevent the axon from being damaged in the first place, early.

 

MSDF

Very good, I appreciate it.

 

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Thank you for listening to Episode Eighteen 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.

 

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Multiple Sclerosis Discovery -- Episode 17 with Dr. Hans Lassmann

Published: Oct. 20, 2014, 5:17 p.m.
Duration: 18 minutes 2 seconds

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Multiple Sclerosis Discovery -- Episode 16 with Dr. Revere "Rip" Kinkel

Published: Oct. 14, 2014, 6:13 p.m.
Duration: 17 minutes 54 seconds

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Multiple Sclerosis Discovery -- Episode 15 with Professor Ludwig Kappos

Published: Oct. 6, 2014, 5:22 p.m.
Duration: 14 minutes 19 seconds

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Multiple Sclerosis Discovery -- Episode 14 with Professor Gavin Giovannoni

Published: Sept. 29, 2014, 6:06 p.m.
Duration: 17 minutes 29 seconds

 

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Multiple Sclerosis Discovery -- Episode 13 with Professor Alan Thompson

Published: Sept. 22, 2014, 11:38 p.m.
Duration: 12 minutes 3 seconds

Now to the interview. Dr. Alan Thompson is the chair of the scientific steering committee of the International Progressive MS Alliance. At the ECTRIMS-ACTRIMS meeting, the Alliance announced their 22 first-round grant recipients. Dr. Thompson met with science writer Cynthia McKelvey to discuss the challenges in researching progressive MS.

Interviewer – Cynthia McKelvey

What is the goal of the Progressive MS Alliance?

 

Interviewee – Dr. Alan Thompson

The goal is very simple; it’s to find treatments for progressive MS, probably the most important thing we have to do in the field of MS now.

 

MSDF

We’re at the ACTRIMS and ECTRIMS meeting in Boston, and tomorrow you’re going to announce the first round of grant recipients. What were you trying to accomplish with this first round?

 

Dr. Thompson

Well this, the RFA one as we call it, was really to stimulate interest in progressive MS; so to encourage as many people around the world to put in applications for these relatively small awards – they’re 75,000 Euros – but it was really to stimulate interest. And it certainly succeeded in doing that in that we had 195 applicants, perhaps double of what we thought. And I think what’s also quite unique about this is this is an international initiative, so the review of these awards was done internationally and agreed by this panel, so that they’ll be announced tomorrow. We were initially hoping we would have 15 awards, but we’ve been able to make 22 awards because of A, the quality of the applications, but also the willingness of the executive committee to actually go a little bit further.

 

MSDF

With this first round in terms of the research, what do you hope to accomplish to eliminate some of the mysteries in progressive MS?

 

Dr. Thompson

We’ve identified a number of areas that we feel are absolutely critical if we’re going to actually identify new treatments. The first is around mechanisms underlying progression and thereby identifying potential targets for treatment. Then, of course, there’s the whole issue of biomarkers and evaluating the effect of treatments, setting up new trials in progressive MS. And the other area is around rehabilitation and symptomatic management, which is really critical for people with progressive MS.

 

And if you look at the range of awards that we’re making, they actually hit all of these areas. So there’s a couple of awards in each one, which is really very reassuring. I mean, I think the hope will be that these could also be the beginning of the major network awards that we’re moving on to in the next phase.

 

MSDF

And my understanding is that in progressive MS, there’s a lot of issues just in doing basic research, and even in moving onto clinical trials. What are some of those issues and how do you propose that research can overcome them?

 

Dr. Thompson

Well, if we look at two areas, I suppose, the first is understanding the basic mechanisms, and what does progression mean, what’s actually happening? Is it driven by inflammation, is it purely neurodegenerative, what’s the combination of those, are there other cells involved like microglia or astrocytes? So there are big questions around mechanisms, which are essential if you’re going to target treatments. And driving that research forward will help us to define new targets. That’s part of the story.

 

The other large area is then, well, how do you measure effect? And progression goes on over many, many years, it is predominantly neurodegenerative so we need to think about different biomarkers; markers of tissue loss or tissue destruction rather than of inflammation, which is, in many ways, much easier and which we’ve been able to apply in relapsing-remitting MS. So that needs to be resolved. And there’s a lot of imaging work going on, and, indeed, other CSF biomarkers being looked at which might help us in that field.

 

And then going on to trials themselves. The current approach to trials is very lengthy, very costly, and not very innovative. And we need to think about news ways of looking at a number of different agents at the same time. And there are already examples, both in Europe and in the United States, where we’re starting to do that. So these are all areas where there’s movement. And I suppose what the Alliance has tried to do is really drive that, focus it and drive it forward in a true collaboration.

 

MSDF

So there aren’t currently, at least in the US, any FDA-approved treatments for progressive MS. What specific types of treatments are you focusing on that you think will be most promising?

 

Dr. Thompson

The treatments we have at the moment which we are you using in relapsing-remitting MS are fundamentally around suppressing inflammation, and that does not appear to be sufficient to have an effect on progression, and that’s probably not surprising. So I think the kind of approaches that we need to take with progression is around neuroprotection and also around repair. And these are more challenging; these are more challenging from a neuroscientific point of view, but also more challenging clinically. But that’s where we would expect the new trials to come out of those areas, particularly around neuroprotection.

 

MSDF

Why is it challenging to study that scientifically?

 

Dr. Thompson

Well, because neuroprotection is a concept at repair that we’re thinking about, not just for MS but for a whole range of neurological conditions, including Alzheimer’s, a motor neuron disease. And it’s challenging because you have to understand the underlying mechanisms and then you have to understand how your intervention is going to alter those. And that’s really getting to the heart of some of the most difficult questions in neuroscience.

 

MSDF

It’s also my understanding that even just confirming that any of these drugs actually work in people is another challenge.

 

Dr. Thompson

Yes. I mean, I think confirmation requires, first of all, a really reliable surrogate marker, but it also requires a clinical measure. And when you’re looking at a process which goes on over 30 years, trying to get a snapshot in two or three years is very difficult. And the clinical measures we have in MS are not very sensitive to change, and so there’s another major initiative called MOSAIC which is actually looking at trying to develop more sensitive measures that we could then apply in trials for progressive MS.

 

MSDF

What is the future for the Progressive MS Alliance? How do you propose to go from this first round of grants towards a cure?

 

Dr. Thompson

The Alliance is a new concept, and the idea of everybody working together internationally to solve a really difficult problem is very exciting. The RFA-1 was encouraging because there was so much interest. So it’s quite clear that in every country from North America to Australia, Europe, Asia, everybody feels this is the key question. So what I would like to see happening is we moving from these smaller grants to this international network of grants. So the RFA-2 will require major centers to come together to address very specific questions. Collaboration is the key for difficult questions, so I think this is the right approach.

 

We’re planning RFA-2 to be very iterative with the scientific steering committee so we can really try and get the very best out of it. This has to be transformational. If RFA-2 is successful and we’re putting three or four major pieces of research forward that will be costing between 4 and 5 million Euros, then we might think about building on that and becoming even more ambitious, drawing in even more resources internationally. And then perhaps – and hopefully – and the final aim, coming up with a treatment for progressive MS.

[transition music]

 

Thank you for listening to Episode Thirteen 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]

 

 

 

 

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 12 with Professor Gavin Giovannoni

Published: Sept. 15, 2014, 5:47 p.m.
Duration: 20 minutes 2 seconds

 

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 11 with Dr. Jack Antel

Published: Sept. 8, 2014, 8:02 p.m.
Duration: 18 minutes 1 second

 

 

Host – Dan Keller

Hello, and welcome to Episode Eleven 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. Jack Antel about remyelination and microglia. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.

 

Our latest data visualization reveals a mystery in relapsing-remitting MS. It appears that the annualized relapse rates of patients in the placebo arms of clinical trials – the placebo arms – have been decreasing since 1993. What could possibly account for this? We invite your hypotheses. Visit the MSDF website and go to our data visualizations page under “research resources.” From there you can connect to a discussion forum we’re hosting to share your opinions.

 

Deep brain stimulation is an extreme brain surgery that can lead to dramatic improvements in patients with Parkinson’s disease or obsessive-compulsive disorder. But in MS patients with tremor, the risk-benefit ratio varies a great deal from patient to patient. The surgery involves placing an electrode into the thalamus and stimulating the surrounding neurons to reduce tremor. However, no one is sure why the procedure works in some people with MS tremor and not in others. Last week, we published a news synthesis—including a dramatic video—on the efficacy of this surgery to treat the otherwise untreatable tremor in some MS patients.

 

We also reported on results from the phase 1 clinical trial of an anti-LINGO-1 remyelination agent. The drug, called BIIB033, is produced by Biogen Idec and proved safe and tolerable in healthy individuals and people with MS. In mouse models, the drug is shown to work by blocking LINGO-1. LINGO-1 prevents oligodendrocyte progenitor cells from differentiating into myelin-producing cells. The company is now conducting a phase 2 study to determine proper dosage in patients with MS.

 

[transition music]

 

Now to the interview. Dr. Jack Antel is a neurologist at the Montreal Neurological Institute and Hospital. His team studies remyelination and repair. He spoke with MSDF about how microglia and progenitor cells affect this process.

 

Interviewer – Dan Keller

Welcome, Dr. Antel.

 

Interviewee – Jack Antel

Thank you very much.

 

MSDF

Where do things stand now? What is the thinking of remyelination? Is it a dynamic process? Is it something that happens all at once? Is there a balance between injury and repair?

 

Dr. Antel

From the perspective of multiple sclerosis itself, we look to our pathologists who've examined the actual MS tissue, and they have established criteria by which they identify that remyelination has occurred, and thus this has been a major incentive to see whether one can accelerate that process. One can now somewhat question the certainty that we are distinguishing between actual remyelination and perhaps partial injury of myelin, and maybe part of what we've seen is actual injury rather than actual repair. The other side of the coin is from the experimental biologist who clearly have shown remyelination to occur and have identified progenitor cells as being the basis of remyelination in animal models. Now we have to bring the observation from the clinical pathology in humans together with those observations are we still certain that all of remyelination is dependent on new cells, or can previously myelinating cells still contribute. And in the context of the human disease, the issue is what is the total potential of the cells? Why doesn't everybody remyelinate? This is because there's intrinsic differences in the myelin cells that humans have. Could the myelin cells themselves be subject to injury? And also, the complicating feature is how much injury is there? So that, if the axons have been damaged, maybe they are not receptive to remyelination. And also, the chronic changes in the environment of all the other glial cells and their products in the human situation, which is after all a disease of months and years not of days and weeks, maybe this is an important influence as to why remyelination occurs or doesn't.

 

MSDF

You had mentioned partial myelination or demyelination. When one looks at a path slide, is it possible to tell whether it's going up or down? Can you distinguish one from the other?

 

Dr. Antel

So that active injury of myelin can be identified because in the active MS lesion myelin debris is freed up and picked up by the phagocytic cells – either the microglia or macrophages – so one can see that there is active injury. If one looks just at the myelin sheath itself, the criteria for remyelination is these sheaths have become rather thinned out, and the segment of the myelin sheath is shorter than in the naturally myelinated cell condition. The issue becomes whether are we absolutely sure that this is remyelination, or could one model developing this histologic feature in some way by injury? And I think that would be a very good challenge for the experimentalists to see if they can get an injury model that reproduces some myelin injury without actually killing the myelinating cells.

 

MSDF

Besides being a target for the immune response, how do glia participate in the immune response?

 

Dr. Antel

So the glia – we can refer both to the astrocytes and microglia – and as you mentioned one of the important issues I think with these cells is how they talk to the immune cells that are coming from the outside into the brain and modulating their properties. In addition, these glial cells themselves can influence the myelination process in several ways. One is that they can produce some of the same molecules that the immune cells produce or novel molecules that can either promote or directly inhibit the capacity of myelinating cells to function – so direct signaling effects on the myelinating cells. The other is they are producing molecules that change the environment so that processes either grow out or don't grow out from the myelinating cells. So we have to consider the glia, which are very dynamic and thus become a target for therapeutic manipulation, in terms of both their effects on immune cells but also can they be so, if you will, "good guys" or "bad guys" in terms of the promoting the myelination process.

 

MSDF

We think of some of the present drugs as modulating the immune system and trafficking and its effect on effector cells. But do you think that some of these may be affecting bystander cells, or I suppose maybe they're not bystanders if they're actively involved. Could they have an affect on glia?

 

Dr. Antel

I think that this is an emerging opportunity in the field because we are now having the first generation of drugs that actually access the central nervous system. The initial generation of drugs, many of the monoclonal antibodies, we felt were acting outside of the nervous system – either on immune cells themselves or on the cells that comprised the blood-brain barrier but with some particularly of the small molecule drugs that access the central nervus system – that these drugs have the capacity to interact with the neural cells. If we use as an example the family of agents that we refer to as this sphingosine-1-phosphate receptor modulators, S1P agents, there has long been data that these receptors are expressed on all cells, including all of the neural cells, and there is existing data that S1P modulators can affect the function of glial cells. Now how this translates into effects that are clinically relevant is the challenge that's ongoing now.

 

MSDF

How does all of this relate to progressive MS?

 

Dr. Antel

So progressive MS, I believe, is an entity that we have not totally understood yet, and we have to consider it in its parts, namely is progressive MS reflective of ongoing injury to the myelinating cells or the underlying axons? Is this a reflection of the injured cells no longer able to maintain themselves are they metabolically failing? And that can we distinguish these processes because if it's ongoing immune injury – whether related to the adaptive or innate immune system – then it makes sense to target those process. If it's an injury or metabolic failure, then that would be another approach. I think we have to consider whether progressive MS, again has evolved over many, many years, and whether one of our challenges is reducing the initial injury process can avoid many of these long-term events.

 

MSDF

In secondary progressive MS, do you see that there's sort of a tipping point? Is there something different in secondary progressive once that occurs?

 

Dr. Antel

It's difficult to provide an answer, and I think here is an area particularly where careful clinical studies are guiding us that the initial notion that multiple events triggered a later process would have been a very nice system to have because then stopping a process early would have predicted a beneficial later response. We are struck that the clinical data is suggesting that progression can occur perhaps even in the absence of ongoing inflammation whether the two are dissociated, at least in some cases, is a real concern. And thus, just controlling the initial immune response – because it triggers a later event – may not be sufficient. And the reverse, which I think has received perhaps less attention, is that from the clinical perspective multiple people have multiple disabling acute events and do not develop the progressive process. So it is not clear that the two are absolutely linked; whether there are genetic susceptibility factors that determine this have not yet emerged; whether it's the nature of the injury; or whether we have multiple diseases processes.

 

MSDF

We often think of bench-to-bedside as the pathway for advancements. Now you had told me earlier that you're working with people in the opposite direction; you're finding things in the human condition and then leading to laboratory validation. Can you tell me a little bit about that?

 

Dr. Antel

I think this is a very important aspect and why it is important that the clinical and clinical pathology experts really identify the core issues so that they can be taken to a laboratory and experimentally addressed. That in MS, we're dealing with a disease that develops over months and years making it more difficult to model it precisely. It's a disease where we have not established the initiating event. Whereas in the animal system, we usually use a arbitrary antigen if we were going to model an immune mediated disorder. We model the demyelination/remyelination process usually by acute toxins in the animal systems; whereas this is not the case in MS that specific exposure. And so I think we need to continue to develop our model systems that can induce some type of progressive disorder that is not specifically introduced perhaps by a specific antigen, at least the antigens we use currently.

 

MSDF

Knowing that remyelination is possible, is there an implication that it may be going on in all of us in healthy brain at all times where you actually get turnover? And if so, can you capitalize on this kind of system?

 

Dr. Antel

So the issue of turnover of myelin, I think, has not been emphasized sufficiently until recently both from the perspective if we have continuous turnover whether this may be one of the mechanisms whereby antigens are presented to the immune system. The other in terms of the turnover rate of myelin or oligodendrocytes – whether the health of these cells is damaged by the disease process, and whether a limiting factor over time is that the injury of the cells, which could be quite subtle – so that the cells are not killed, but they've impaired their function either to maintain the interaction with axons or the necessary transport of key molecules down the processes. Whether interruption of this then results in the inability of the cells to maintain their myelination properties and to continue the turnover or what might be a repair activity. And we interpret this as a later progression of the disease.

 

MSDF

On the topics we've been discussing, is there anything important to add?

 

Dr. Antel

I think the importance is that we now are turning our attention to these topics. That it is very timely that we do this – because until we could control the actual disease activity through immunomodulatory therapies – if that aspect was not controlled it would be much more difficult to think of trying to control the overall disease process. And also, as we couple the biology with careful clinical observations and the advances in imaging of the human brain, so that it gives us greater opportunities to bring our theories from the lab to the clinics and see whether we really impact in a positive way on the processes we've been discussing.

 

MSDF

Very good. We appreciate it.

 

Dr. Antel

My pleasure.

 

[transition music]

 

MSDF

Thank you for listening to Episode Eleven 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]

 

 

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]

 

 

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 10 with Dr. Richard Ransohoff

Published: Sept. 1, 2014, 5:56 p.m.
Duration: 22 minutes 38 seconds

Listed in: Health

Multiple Sclerosis Discovery -- Episode 9 with Dr. Amit Bar-Or

Published: Aug. 25, 2014, 5:23 p.m.
Duration: 22 minutes 26 seconds

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 8 with Dr. Wendy Macklin

Published: Aug. 19, 2014, 5:50 p.m.
Duration: 15 minutes 49 seconds

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 7 with Dr. Daniel Kantor

Published: Aug. 11, 2014, 4 p.m.
Duration: 15 minutes 9 seconds

Listed in: Health

Multiple Sclerosis Discovery -- Episode 6 with Dr. Jeffrey Dunn

Published: Aug. 4, 2014, 4:48 p.m.
Duration: 20 minutes 22 seconds

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 5 with Dr. Anne Cross

Published: July 28, 2014, 4:17 p.m.
Duration: 16 minutes 24 seconds

Listed in: Health

Multiple Sclerosis Discovery -- Episode 4 with Dr. Michael Racke

Published: July 21, 2014, 3:58 p.m.
Duration: 12 minutes 1 second

Listed in: Health

Multiple Sclerosis Discovery -- Episode 3 with Drs. Daren Austin and Susan Van Meter

Published: July 14, 2014, 5:07 p.m.
Duration: 16 minutes 40 seconds

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Listed in: Health

Multiple Sclerosis Discovery -- Episode 2 with Dr. Barbara Koppel

Published: June 23, 2014, 11:02 p.m.
Duration: 16 minutes 25 seconds

Listed in: Health

Multiple Sclerosis Discovery -- Episode 1

Published: June 6, 2014, 9:03 p.m.
Duration: 17 minutes 1 second

Listed in: Health