Repairing the Nervous System: Remyelination and Multiple Sclerosis

Acute inflammatory demyelination, limited remyelination, progressive axonal loss, and development of multifocal sclerotic plaques—this is the typical sequence of injury to the brain in patients with multiple sclerosis (MS). For patients, this translates into a difficult-to-predict course of sometimes benign but often debilitating inflammatory attacks that are commonly followed by degenerative decline. For physicians, it represents one of the most common reasons for neurologic referral, a major cause of disability in their young adult patients, and a heterogeneous and enigmatic neurologic disease.

MS occurs when a confluence of poorly characterized genetic and environmental factors initiates an immune-mediated response directed at brain components. T cells break through the blood-brain barrier, mistakenly identify healthy myelin-producing cells or their myelin products as foreign, and attack and destroy them.

Symptomatic treatments are often successful, but no treatment can stop the progression of the disease. As Claudia F. Lucchinetti, MD, a neurologist and MS researcher at Mayo Clinic in Rochester, Minnesota, puts it, "We're still at a point where many patients worsen, despite therapies that impact the inflammatory aspect of the disease. So the focus of MS research is understanding why this occurs and what can be done about it."

Downregulating the Immune System—Positive or Negative?

Paradoxically, the inflammatory immune response that produces demyelination also induces remyelination, a natural repair process of demyelinated tissue. Natural remyelination is spotty, patchy, and limited in the central nervous system (CNS). Yet suppressing inflammation may prevent it altogether.

Twenty years ago, when the idea that the CNS could repair itself was unheard of, Moses Rodriguez, MD, a Mayo Clinic neurologist and researcher, was trying to prove that stimulating the immune system would aggravate an MS-like illness in animals. In fact, the animals' condition improved and they showed evidence of remyelination, indicating CNS repair not only was possible, but also was enhanced by increased inflammation directed against the CNS. Converging lines of evidence, including brain biopsy and autopsy tissue analysis, confirmed that remyelination, as well as demyelination, occurs in humans with MS.

Today, uncovering the mechanisms of successful and unsuccessful remyelination in MS is considered a critical step in preventing disease progression. Myelin sheath destruction results in acute, usually transient and reversible inflammatory attacks that interfere with axonal conduction of neuronal impulses. But failure to remyelinate eventually leads to axonal death and the chronic, irreversible motor, sensory, and cognitive deficits of late-stage MS. It is this chain of events—from acute attack to downstream destruction—that Mayo researchers want to prevent.

Two Phases of MS, Two Patterns of Tissue Injury

The Inflammatory Acute Phase
The early phase of MS is characterized by intense inflammation, focal demyelination, and limited remyelination during acute attacks of neurologic dysfunction. It occurs in the context of T-cell invasion across the blood-brain barrier. Axons may or may not recover during this phase. Symptoms are treated with varying degrees of success by immunosuppressive, anti-inflammatory, or immunomodulatory drugs, alone or in combination. Plasma exchange, first studied in a controlled trial at Mayo Clinic as a possible "rescue therapy" for catastrophic refractory episodes, is effective in some forms of MS.

The Chronic Progressive Phase
There is no treatment for the chronic progressive phase. Not only myelin, but also neurons are injured in the cerebral and cerebellar cortices. Global tissue destruction in chronic MS occurs in the context of a relatively intact blood-brain barrier. Because the process is compartmentalized in this way, it is likely less accessible to the effects of anti-inflammatory or immunomodulatory treatments.

The smoldering inflammation, demyelination, and axonal injury of this phase probably begin during earlier inflammatory attacks. The process affects demyelinated plaques as well as normal-appearing white matter. Wallerian degeneration and loss of trophic support from growth factors associated with healthy oligodendrocyte cells are likely involved. Researchers believe that perturbed interactions between axons and myelin sheaths interferes not only with conduction and remyelination, but also with axonal outgrowth and connectivity. Eventually demyelination disturbs the delicate balance and complex physiology of the entire CNS.

Brian G. Weinshenker, MD, a neurologist and MS researcher at Mayo Clinic, reports that patients often see the change from the acute to the chronic phase as an abrupt switch. However, even in early MS, MR spectroscopy shows reduction of axonal density. The brain has considerable reserves, but at some point, axonal death reaches a tipping point, and patients begin to experience progressive loss of neurologic function.

The question is, can it be prevented and, if so, how? The answer may lie in therapeutic remyelination.

Remyelination: Keeping Axons Alive

Remyelination keeps axons alive, but natural remyelination is limited. Could the process be stimulated therapeutically? Even without reestablishing conduction, keeping axons alive might limit or prevent the diffuse damage and lasting disability of chronic MS.

Therapeutic remyelination has become a beacon of hope, and the team of MS neuroscientists and neurologists at Mayo Clinic are in the forefront of research to make it a reality.

Patterns of Natural Remyelination
Are some people better at remyelination than others? It turns out they are. The MS Lesion Project, funded by the National Multiple Sclerosis Society and led by Dr Lucchinetti and a diverse international group of collaborating scientists, identified more than 700 people with MS who underwent brain biopsies. From these data, they discovered not only evidence of remyelination, but 4 distinct MS subtypes. Two show evidence of good natural remyelination. Two do not. In a separate study funded by the National Institutes of Health, Dr Lucchinetti and colleagues are investigating whether genetic predisposition contributes to successful natural remyelination.

A schematic of an IgM antibody. An IgG would consist of just one of the subunits.

Antibody 22, a Key to Remyelination
Early thinking about therapeutic remyelination focused on transplanting cells such as oligodendrocyte progenitor cells and on administering neurotrophic growth factors. However, there are numerous unresolved issues in cell transplantation, and growth factor strategies have had serious adverse effects and disappointing results.

Dr Rodriguez, Larry R. Pease, PhD, and colleagues were on another track—the search for natural human monoclonal antibodies that would promote repair. Some of these antibodies are involved in the demyelination; some in remyelination. As Dr Rodriguez says, "Each MS lesion is its own little world composed of destructive and protective factors. We tried to enhance the reparative factors."

In 2001, as Dr Lucchinetti's team was uncovering MS subtypes, Dr Rodriguez and his colleagues discovered the natural monoclonal autoantibody they were after. Unlike the antibodies made by industry to fight cancer, it is an immunoglobulin of the M type (an IgM). They labeled it "number 22." Then, using DNA from the patient in whom they discovered it, they sequenced and reproduced it in recombinant form.

Number 22 differs from other antibodies. First, it is an IgM, the largest type of antibody with 5, rather than 2 binding sites. Second, it occurs naturally in many individuals and species and is very primitive in evolutionary terms. It is the body's first and most rapid line of defense, often referred to as the "innate immune response." Because it is natural, it carries few if any adverse effects, unlike industry-synthesized IgGs. Dr Rodriguez and his team found that it promoted remyelination in approximately 50% of lesions in mice with a virus that mimics MS and was effective in more than 85% of animals tested. They immediately set about producing enough to take to human trials. Now, in conjunction with a Good Manufacturing Practices facility at the University of Minnesota, they have made enough to be steps away from a US Food and Drug Administration–approved phase 1 clinical trial to test the safety of this antibody in humans.

Photomicrograph of mouse spinal cord with demyelinating disease

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The Next Steps: Taking Remyelination to Clinical Trial

The Right Patients at the Right Time
The next steps are equally critical. As Dr Weinshenker says, "To be successful, we need a great tool, and we need the right patients at the right time. The challenge is to find them." The right time is early in the disease when it is amenable to treatment. The right patients would seem to be patients who are "good natural remyelinators" who fall into the 2 MS subgroups in which oligodendrocytes and/or progenitor cells are available to respond to IgM number 22. It is important to identify patients with the potential to repair using noninvasive tools. In the past year, the MS Lesion Project has found a strong correlation between evidence of remyelination on biopsy and a pattern of "ring enhancement" in MS lesions that shows up on MRI scans. This finding could greatly enlarge the pool of candidates for clinical trials.

Measuring Outcomes

• Is there a critical period for remyelination?
• Are factors affecting endogenous remyelination the same in the acute and chronic phases of the disease?
• How much myelin is needed for success?
• How many axons need to be repaired to prevent diffuse tissue damage?
• Can axon outgrowth be promoted through remyelination?

Answers to these questions rest on the ability to measure an outcome, which itself interacts with timing and patient selection. For example, in the short run, patients who are good remyelinators may remyelinate almost as well without treatment. The goal, however, is to prevent chronic degeneration, a process that may take years, so clinical signs must be combined with other objective measures of outcome. To monitor outcome, Mayo neuroradiologists, led by Bradley J. Erickson, MD, PhD, are developing ever more refined, innovative techniques such as identifying ring enhancement on MRI and increased levels of N-acetyl aspartic acid (NAA) by MR spectroscopy.

The Potential Impact of Remyelination

Multiple sclerosis affects 1 in 1,000 people in the Western world. Mayo Clinic in Minnesota sees more than 1,500 new cases of MS a year. Across its 3 campuses, Mayo Clinic has a team of specialists who have devoted their careers to the study and treatment of MS. Remyelination may be an important step in that direction. With a laboratory focused on the pathologic factors contributing to early and late disease, another invested in developing remyelination strategies, with a potentially effective antibody in production, and an imaging team devoted to finding a way to measure outcomes, Mayo Clinic is positioned to discover whether the promise of remyelination holds true.

Dr Weinshenker says, "If we are 80% successful in reducing or repairing lesions, we're going to have a very big impact, one that might very well prevent patients from progressive disease down the line." Dr Rodriguez anticipates that IgM antibody number 22, if successful, may be a major step toward therapeutic nervous system repair not only in patients with MS but also potentially for those with other degenerative CNS diseases and spinal cord injury. Aware of the challenges ahead, Dr Lucchinetti sees saving axons as one of the best means of preventing intractable disability in patients who "are getting worse, despite therapies that impact the inflammatory aspect of the disease."