Nerve Repair Teams Convened to Share Exciting Progress and Plan Next Steps - National Multiple Sclerosis Society

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Nerve Repair Teams Convened to Share Exciting Progress and Plan Next Steps

January 26, 2011

A cure for MS means not just stopping and ending the disease but repairing damage and restoring lost function. The Nervous System Repair and Protection Initiative, funded through the National MS Society’s Promise: 2010 Campaign, was launched in 2005 to address what was then an underexplored area. This bold initiative involved the largest grants ever offered by the Society and set the stage for translating basic lab discoveries into clinical efforts to restore nerve function in people with MS. The results have been impressive: it jump-started the field, trained scores of promising young investigators, produced over 150 research papers, and leveraged millions of dollars in new funding.

These four multinational, interdisciplinary teams met recently in New York City to discuss their accomplishments during the last five years, and to look toward the future. “It’s remarkable,” said Timothy Coetzee, PhD, Chief Research Officer of the National MS Society. “We launched this initiative to set the stage for clinical trials of neuroprotection in MS, and five years later, we are seeing these studies come to life.”

Repair and Protection: What they mean

During the course of MS, the immune system attacks the brain and spinal cord. Nerve cells have wires, or axons, that allow them to send and receive signals. The axons have a coating on them, which can be likened to insulation on a wire, which nourishes the axons and speeds nerve conduction. That coating is myelin. Myelin is a main target in MS, but axons are also damaged. Damage to axons is probably what causes progressive disability or worsening in people with MS. The focus of “protection” efforts is to stop the destruction of myelin and axons; the focus of “repair” efforts is to restore those tissues.

Drs. Peter Calabresi (Johns Hopkins University, Baltimore), Ian D. Duncan (University of Wisconsin, Madison), Charles ffrench-Constant (University of Edinburgh) and Gavin Giovannoni (Queen Mary University of London) and their team members reported on their progress in all three goals of the repair initiative with the ultimate goal of paving the way for clinical trials to protect the nervous system, repair the damage and restore function in people with MS. Read more about the four teams.

Goal 1: Develop new disease models to screen repair and protection techniques

Team members made great strides in developing new tools to investigate myelin damage and repair. It is now possible to grow nerves and myelin-making cells in lab dishes and explore molecular signals engaged in repair. New treatment strategies cannot be tested without therapeutic targets being discovered and without the development of animal models for testing safety and effectiveness before studies can begin in people. Teams reported numerous exciting developments in this goal area.

Key Take-aways:

  • New therapeutic targets have been identified from extensive screens of tissue culture systems and genes and proteins; early tests in rodents promising.
  • There have been exciting pre-clinical breakthroughs in cell-based therapies.
  • A mouse model of secondary-progressive MS is established and being used to test therapeutic candidates.

Investigators used the latest in “omics” technology – such as genomics, which screens multiple genes simultaneously – to identify new targets for MS therapies. Drs. Stephen P. J. Fancy, David Rowitch (University of California, San Francisco [UCSF]), Robin J. M. Franklin (Cambridge University, UK) and colleagues conducted high-tech screens to detect the activity of genes, called transcription factors, that control other genes. Among 1,040 transcription factor genes that were active in mice during the process of myelin repair, they pinpointed the “Wnt signaling pathway.” Further experiments showed that this pathway may play an important role in the failure of myelin to repair itself in people with MS. Read more about this study. (internal link to Jul 13, 2009 News Story)

Drs. Jeffrey K. Huang (Cambridge), ffrench-Constant, Franklin and colleagues created a “transcriptome” – a complete picture of RNA activity during spontaneous myelin repair. RNA, ribonucleic acid, is the chemical that delivers the instructions from a gene to a cell. The results showed high levels of activity for the gene that controls a molecule called retinoid acid receptor-gamma, and further study showed that this molecule that appears to stimulate the brain’s natural ability to repair myelin in rodents. Read more about this study. (internal link to Dec 07, 2010 news story)

Investigators funded through this initiative have propelled research on cell-based therapies forward, reporting groundbreaking results. Dr. Steven A. Goldman and colleagues (University of Rochester, NY) transplanted human immature myelin-making cells into mice born without myelin, resulting in widespread myelin formation and restoration of neurological deficits. Read more here. (internal link to Jun 05, 2008 news story) Dr. Gianvito Martino and colleagues (San Raffaele Scientific Institute, Italy) transplanted nerve stem cells into models with MS-like disease, stimulating repair and reducing inflammation. (Stem Cells. 2007 Oct;25(10):2583-92) This team is nearing a phase 1 study of this strategy in people with MS.

Drs. Siddharthan Chandran (Cambridge), David Baker (Queen Mary) and colleagues studied the “Biozzi” mouse model, and confirmed that this is the model of choice for studying secondary-progressive MS. The model replicates the chronic myelin damage and nerve fiber loss found in later phases of MS, without the inflammation of early disease. This is an invaluable tool for studying the safety and benefits of neuroprotective drugs in progressive MS. (Journal of Neuroimmunology 2008 Sep 15;201-202:200-11)

Dr. Duncan and colleagues studied a model where a neurological disease can be induced and resolved through spontaneous repair, restoring neurological function to normal; this model will help to understand the natural mechanisms of repair and how they translate to symptoms experienced by people with MS. (Proceedings of the National Academy of Sciences U S A. 2009 Apr 21;106(16):6832-6) In a truly exciting effort, Dr. Franklin and collaborators showed that cells from young mice could enhance myelin repair in older mice, giving us new information on a possible role of aging in nervous system damage, and new possibilities for inducing repair. (Nature Neuroscience 2008 Sep;11(9):1024-34)

Goal 2: Apply advanced MRI and other non-invasive monitoring tools to detect nervous system protection and repair

What if a new therapy was developed to protect brain cells from damage and even regenerate new cells to repair damage caused by MS, but there was no way to prove that it works? Developing ways to measure damage and repair was another goal of this initiative, with results ranging from simple tests of function to cutting edge technology.

Key Take-aways:

  • A simple, quick eye test, OCT, has been validated as a method of showing nerve fiber damage and health.
  • Novel imaging technologies (DTI, MT) can specifically detect myelin and nerve fiber damage and track it over time.
  • Possible biological marker of disease progression found in spinal fluid.
  • Simple functional tests may correlate with underlying disease activity and hold promise for use in clinical trials.

Laura Balcer (University of Pennsylvania), Elliott Frohman (Southwestern Medical Center, Dallas), and Calabresi, Lauren Talman, and colleagues confirmed that optical coherence tomography, or OCT, can measure the health of the nerve fibers in the back of the eye. This simple, quick method can show how much nerve fibers in the eye are damaged. Changes can be observed in people with MS, even if they don’t have eye inflammation. (Annals of Neurology 2010 Jun;67(6):749-60) Drs. D.M. Harrison (Johns Hopkins), Calabresi, Daniel Reich (NIH), and colleagues showed that other novel imaging technologies – such as diffusion tensor imaging (DTI), which measures the flow of water particles in tissue, and magnetization transfer, which measures the transfer of energy particles – could specifically detect myelin and nerve fiber damage and track them over time. These methods will be useful in tracking treatment success or failure during clinical trials. (Neurology. 2011 Jan 11;76(2):179-86)

Drs. Sharmilee Gnanapavan (Queen Mary) and Giovannoni searched for biomarkers that would indicate tissue damage or repair via a blood or spinal fluid sample. This research has indicated several possibilities, including neurofilament, a threadlike molecule found in nerve cells that can be measured in spinal fluid. Neurofilament levels may be a good indication of whether nerve cells are being damaged, and whether disease is progressing. If validated in further research, measuring neurofilament may prove to be a quick measure of whether potentially neuroprotective drugs are working, enabling faster clinical trials.

Drs. Aaron Field, Andrew Alexander (University of Wisconsin-Madison) and colleagues reported on an effort to combine DTI and diffusion spectrum imaging, which enabled them to examine nerve fibers that intersect each other. The team has been able to minimize the imaging time necessary for this hybrid approach and increase its accuracy.
(Neuroimage. 2011 Feb 1;54(3):1840-53)

Scientists also reported progress in using clinical tests that can assess symptoms simply, but may correlate with underlying disease activity. For example, Drs. Kathleen M. Zackowski, Calabresi (Johns Hopkins) and colleagues showed that “sensorimotor” dysfunction that was picked up by testing vibration sensation and ankle strength correlated with disease activity on advanced MRI technology. (Brain. 2009 May;132(Pt 5):1200-9) Also, Dr. Balcer’s research indicates that tests of visual acuity (perception of light gray letters of progressively smaller size on a white background) correlate with OCT and other imaging results. These tests may be quick, simple ways of measuring outcomes in clinical studies.

Goal 3: Design human clinical trials of repair and protection therapies.

The ultimate goal of this initiative was to lay the groundwork for clinical trials of strategies to protect and repair the nervous system: Mission accomplished.

Key Take-aways:

  • Clinical trials are underway, or being planned, to evaluate experimental strategies for nervous system protection and repair.
  • New clinical trial designs and outcome measures are in development to speed up the testing of promising agents.
  • Collaborations are expediting and enhancing the quality of clinical research.

Here is a sampling of studies that are underway or planned in collaboration with team members of this initiative:

  • Dr. Chandran has completed A Phase 1 safety study of mesenchymal cells in optic neuritis. Results are nearing publication.
  • Dr. Rowitch is conducting an industry-backed Phase 1 study to study the safety of neural stem cell transplantation in children born with a lack of myelin; this small, early study would also serve as a “proof of principal” for this strategy in MS.
  • Dr. Raj Kapoor (National Hospital for Neurology and. Neurosurgery, Queen Square, London) is launching a Phase 2 study of phenyltoin to determine its effects on neuroprotection in optic neuritis (funded by the National MS Society and the MS Society of Great Britain and Northern Ireland); the study design takes lessons learned from a failed study of lamotrigine in SP MS. (Lancet Neurology 2010 Jul;9(7):681-8) Both these drugs are sodium channel blockers, drugs that enable tiny pores along nerve fibers to improve nerve impulse conduction.
  • Dr. John Zajicek (Peninsula Medical School, Plymouth, UK) and colleagues are expected to report results later this year from a large multicenter study exploring whether cannabis can slow disease progression in 500 people with primary-progressive and secondary-progressive MS.
  • Dr. Reich and colleagues are beginning NIH-funded studies of the antioxidant idebenone for PP MS and the monoclonal antibody rituximab for SP MS; studies will collect much data on these types of MS as well.

The initiative also has spawned important progress aimed at enhancing clinical research in this area. Team members are among those involved in a new clinical trials network in the United Kingdom to speed up the translation of neuroprotective therapies for people with progressive MS. And guidelines were established for the design and conduct of clinical trials using cell therapies in MS, in collaboration with some team members and several MS Societies worldwide.

The Value of Collaboration

Team leaders unanimously agreed that this collaboration has moved the field of repair in MS forward exponentially.

“The kind of infrastructure that we’ve established is helping to move things forward more quickly,” said Dr. Calabresi of his team. “We can specialize, much in the way a factory does. No one scientist has to think about all the problems that are necessary to move a target, validate it and then get it into clinical trials.”

Dr. ffrench-Constant agreed. “Two things we've done have made a huge difference. We've used the internet extensively to keep everybody in contact. Also, we've recruited post docs and graduate students who have spent time in all of the different labs. This increases the amount of collaboration, and secondly, it trains the next generation of the scientists that we need in multiple sclerosis.”

As the research continues and proceeds towards clinical trials of new MS treatment strategies, team leaders and members were eager to see the momentum continue, and provided several suggestions for further collaborations, including:

  • Hold future nerve repair conferences (investigators have been meeting every two years)
  • Create a shared resource that produces stem cells for all stem cell clinical trials.
  • Develop an initiative comparing the value of different types of imaging technology in monitoring repair.
  • Find creative ways to continue encourage young researchers to enter this field.

Dr. Giovannoni emphasized the importance of investigator meetings in particular. “A meeting focused on repair, just by itself, is a catalyst for further innovation. A lot comes out of these meetings in terms of ideas, hypotheses, and exchanges of research.” Dr. Duncan concurred. “You hear colleagues present interesting information and you realize that you’re quite close; it would just take some kind of joint experiment between the two of you sharing the expertise.”

Dr. Coetzee noted that the Society is evaluating program outcomes to determine how to sustain the momentum created by these teams. “We are going to continue to move our work forward and share it worldwide in order to continue to speed research to repair the nervous system in MS. The dream is stopping MS in its tracks and of restoring function that has been lost. This is topmost in the hearts and minds of people who have MS, as well as their loved ones.”

For more on this topic, watch a webcast, “Repairing the Nervous System in MS: Progress and Next Steps,” (internal link) featuring Dr. Coetzee and the Repair Initiative team leaders.

About Multiple Sclerosis

Multiple sclerosis, an unpredictable, often disabling disease of the central nervous system, interrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.3 million people worldwide.

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