Multiple Sclerosis Nerve Repair Report

Multiple Sclerosis Nerve Repair Report 

A. Problem Specifics

A Multiple Sclerosis (MS) cure does not mean just stopping research because the disease is over with nothing left to do but repair damages and re-claim lost physical functions. The Nervous System Repair and Protection Initiative, funded through the National MS Society's Promise 2010 Campaign, were launched in 2005 to address what was, then, an under-explored 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 Multiple Sclerosis.

The results have been nothing short of impressive. It jump-started the field, trained scores of promising young investigators, produced more than 150 research papers and leveraged millions of dollars in new funding. "It's remarkable," said Timothy Coetzee, Ph.D., Chief Research Officer of the M. S. Society. "We launched this initiative to set the stage for clinical trials of neuro-protection in MS and now, five years later, we are seeing these studies come to fruition." The results have been remarkable.

B. Causes and Symptoms

During the course of MS, the immune system attacks the brain and spinal cord. Nerve cells have wires (axons) that allow them to send and receive signals. Axons have a coating on them called myelin (insulation) which speeds nerve conduction and transmission. Myelin is the main target in MS but axons are damaged, as well, which is probably what causes progressive disability. The focus of efforts in the protection of these cells is to stop the destruction of myelin and axons while the focus of the repair-efforts is to restore the tissues involved.

Dr. Peter Calabresi with Johns Hopkins University in Baltimore, Dr. Ian D. Duncan with the University of Wisconsin in Madison, Dr. Charles Constant with the University of Edinburgh and Dr. Gavin Giovannoni at Queen Mary University of London and their teams reported on their progress in all three goals of the repair initiative. The ultimate goal is to pave the way for clinical trials leading to the protection of the nervous system, to repair the damage that may have been caused and to the restoration of physical abilities and functions in people with MS.

C. Design Goals of Experimentation

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

Some of the teams have made great strides in developing new tools to investigate myelin-damage and to repair this damage. It is now possible to grow nerves and “myelin-making” cells in laboratory 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 using human beings.

In brief:

•    New therapeutic targets have been identified from extensive screens of tissue culture systems, genes and proteins. Early tests using rodents have been very promising.

•    There have been exciting pre-clinical breakthroughs in “cell-based” therapies.

•    A “mouse-model” of secondary-progressive MS has been established and being used to test therapeutic candidates.

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Investigators used the latest in technology such as genomics which screens multiple genes simultaneously to identify new targets for MS therapies. Dr. Stephen P. J. Fancy and Dr. David Rowitch at the University of California (San Francisco), Dr. Robin J. M. Franklin at Cambridge University and colleagues conducted exper-iments to detect the activity of specific 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 pathway to a network of proteins best known for their roles in embryo-genesis (embryo-development) and cancer as well as in normal physiological processes in adult animals. Further experi-ments showed that this pathway may play an important role in the failure of myelin to repair itself in people with Multiple Sclerosis.

Doctor Jeffrey K. Huang at Cambridge University and his colleagues have created a complete picture of ribonucleic-acid (RNA) activity during spontaneous myelin repair. (RNA is the chemical that delivers instructions from a gene to a cell.) 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 appears to stimulate the brain's natural ability to repair myelin in rodents.

Investigators funded through this initiative have propelled research on cell-based therapies with ground-breaking results. Dr. Steven A. Goldman and colleagues at the University of Rochester in New York trans-planted human immature myelin-making cells into mice born without myelin, resulting in widespread myelin formation and restoration of neurological deficits. Dr. Gianvito Martino and colleagues at Italy's San Raffaele Scientific Institute transplanted nerve stem cells into models with MS-like disease, stimulating repair and re-ducing inflammation. This team is nearing a phase I study of this strategy in people with MS.

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. In a truly exciting effort, Dr. Franklin and collaborators showed that cells from young mice could enhance myelin repair in older mice, giving new information on a possible role of aging in nervous system damage and new possibilities for inducing repair.

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

Developing ways to measure damage and repair was another goal, with results ranging from simple tests of function to cutting-edge technology.

In brief:

•    A simple, quick eye test has been validated as a method of showing nerve fiber damage and health.

•    Novel imaging technologies can detect myelin and nerve fiber damage and track it over time.

•    A possible biological marker of disease progression has been found in human spinal fluid.

Laura Balcer with the University of Pennsylvania, Elliott Frohman with The University of Texas Southwestern Medical Center in Dallas and Dr. Peter Calabresi, Lauren Talman and colleagues confirmed that optical coher-ence tomography (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 do not have eye inflammation.

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Dr. D. M. Harrison at Johns Hopkins University, Dr. Daniel Reich at the National Institutes of Health, Dr. Calabresi 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.

Scientists also reported progress in using clinical tests that can assess symptoms simply but may correlate with underlying disease activity. Drs. Kathleen M. Zackowski, Calabresi and colleagues showed that "sensori-motor" dysfunction that was picked up by testing vibration sensation and ankle strength correlated with disease activity on advanced MRI technology. Also, Dr. Baker's research indicates the tests of visual acuity-perception of light gray letters of progressively smaller size with a white background correlate with both optical-coherence tomography (OCT) and other imaging results.

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.

In brief:

•    Clinical trials are underway 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.

Studies are underway or planned in collaboration with team members of this initiative include:

• Dr. Rowitch is conducting an industry-backed Phase I study to study the safety of neural stem cell trans-plantation in children born with a lack of myelin; this small, early study would also serve as a "proof of principal" for this strategy.

• Dr. Raj Kapoor with London's National Hospital for Neurology and Neurosurgery is launching a Phase II study of “phenyltoin” to determine its effects on neuro-protection 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”.  Both these drugs are sodium channel blockers, drugs that enable tiny pores along nerve fibers to improve nerve impulse conduction and transmission.

D. Futures and Expectations

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

Dr. Coetzee noted that the MS 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 and to continue to speed research to repair the nervous system in MS patients. The dream is to stop MS in its tracks and to restore function that has been lost. This is topmost in the hearts and minds of people who have Multiple Sclerosis as well as to their loved ones."

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