"The history of scientific discovery is very often the result of an experiment that goes completely contrary to expectations."

So says Mayo Clinic neuroscientist Moses Rodriguez, M.D.--and he should know. Two decades ago he tried to confirm an accepted theory about multiple sclerosis (MS). He was testing the theory that stimulating the immune system would aggravate an MS-like virus in laboratory animals. However, rather than getting worse, the animals improved. Undaunted by this reversal, Dr. Rodriguez reconsidered his results because he believed that nerve cells or neurons in the brain could, in fact, repair themselves. It turns out that he was right.

Today, converging lines of evidence, including brain biopsy and autopsy tissue at Mayo Clinic, have confirmed that repair following some types of brain damage does occur, particularly in the type caused by MS.

A Paradox and an Enigma

First described over 160 years ago, MS is one of the most enigmatic and paradoxical of neurologic diseases. Scientists are hard pressed to explain its shifting course and the variability between patients. Treatments relieve symptoms early in the disease, but are unable to stop the progression later. The mechanisms of tissue destruction early on may be very different from those in late-stage MS. The paradox is that the very factors that cause symptoms may also help to relieve them.

Claudia Lucchinetti, M.D., has been working to solve these apparent contradictions throughout her career. Her interest in MS began in the mid-1980s when she arrived at Mayo as an 18-year-old summer intern to work with Dr. Rodriguez. She was his first student and has been working with him ever since. Today, she and Dr. Rodriguez head separate laboratories at Mayo Clinic in a coordinated effort to develop restorative therapies. Dr. Rodriguez's findings in animal models of brain repair and Dr. Lucchinetti's in human MS pathology feed back and forth between their labs, translating discoveries into clinical possibilities.

Demyelination

MS is thought to be an autoimmune disease in which the immune system attacks the protective covering of axons, called the myelin sheath. The immune system is organized to defend against infections, viruses and other pathogens. In autoimmune diseases, the system misidentifies healthy tissue as foreign and attacks it.

Axons extend out from neurons like cables, transmitting messages in the form of electrical signals from one neuron to another, thereby enabling the brain to conduct its functions. Wrapped around the axons, the myelin sheath protects and supports axons and enables efficient signal transmission (see figure1A). Without myelin, the brain functions they support become impaired. This process is called demyelination and is the primary destructive process in MS. Eventually denuded axons die off and disintegrate.

Identifying Remyelination in Humans

When the immune system attacks myelin, the body produces an inflammatory response that causes demyelination. Yet, as Dr. Rodriguez and his team discovered in laboratory mice, the inflammation that demyelinates axons also induces a process of repair called remyelination--which explains the paradox of the mice improving when inflammation was induced. Remyelination was limited and patchy in the mice tested, but it did occur. The question was whether it also occurs in humans. If so, could it be harnessed for treatment of MS?

Armed with these findings, Dr. Lucchinetti, leading an international group of collaborating scientists in the MS Lesion Project, identified over 700 people worldwide with MS who underwent brain biopsies. From these tissue samples, they discovered evidence of remyelination in humans. In the process they also uncovered four distinct patterns of tissue destruction in MS. These subtypes explain some of the variability of symptoms between patients. Two of the MS patterns showed evidence of strong natural remyelination. Two did not. They also found that strong remyelination in a given patient in the early-stage MS may not translate into good remyelination in late-stage MS.

Two Phases of MS

Early-stage MS is characterized by intense inflammation, localized demyelination, and limited remyelination. The transient nature of these attacks is due to remyelination, and symptoms at this early stage are treated with varying degrees of success by drugs that suppress or modulate the immune response in an effort to decrease inflammation.

There is, however, no treatment for the motor, sensory and cognitive deficits of chronic, late-stage MS. It appears that when too many axons die the delicate balance and complex physiology of the entire brain is disturbed, eventually causing widespread tissue damage. When the tipping point is reached, patients begin to experience progressive and permanent loss of neurologic function.

The Discovery of Antibody Number 22--the Key to Remyelination

Remyelination keeps axons alive, and keeping them alive may protect against the irreversible progression of MS. Early thinking about therapeutic remyelination focused on cell transplantation and growth factor strategies. However, both methods have had disappointing results. Dr. Rodriguez and Larry R. Pease, Ph.D., Chair of Mayo Clinic's Department of Immunology, and their 20 colleagues pursued another track--the search for a natural human autoantibody, or immune-based protein, that promotes the natural repair they discovered.

In 2001, as Dr. Lucchinetti's team was uncovering MS subtypes, Dr. Rodriguez and his colleagues discovered the natural autoantibody they were after. They labeled it "Number 22." Number 22 is larger and differs in shape from other antibodies. Most important, as Dr. Rodriguez explains, unlike pharmacological or industry-produced antibodies, it is natural to the body, found across species, and is considered very old and 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 side effects, unlike industry-synthesized antibodies. After years of searching, they identified it in a single patient. Then they set about to sequence, reproduce, and test it.

They found that it promoted remyelination in approximately 50% of lesions in mice with a virus that mimics MS, and was effective in greater than 85% of animals tested (figure 1B). They immediately set about producing enough of it to take to human trials.

Antibody Number 22 in Clinical Trial

In conjunction the University of Minnesota, and with funding from the Minnesota Partnership for Biotechnology and Medical Genomics, the team has produced enough antibody to be steps away from an FDA approved Phase I clinical trial to test its safety in humans, scheduled for 2008.

Designing a clinical trial is a complex process. It is not enough to have a good therapeutic tool such as autoantibody Number 22. It needs to be tested in the right patients, at a time when the disease is amenable to treatment, with measurable outcomes that prove it effective.

Identifying the right patients--those in whom there is greater than 80% natural remyelination--needs to be done using non-invasive tools such as brain imaging. For this work, and for measuring outcomes, Mayo is fortunate to have Bradley Erickson, M.D., Ph.D. and his team of neuroradiology researchers. In the past year, they found a strong correlation between evidence of remyelination on biopsy and a pattern of "ring enhancement" in MS lesions that shows up on magnetic resonance imaging (MRI). This finding could greatly enlarge the pool of candidates for clinical trials.

An ability to measure outcomes is essential to answer the following questions:

• Is there a critical period for remyelination?
• Are factors that produce natural 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?

In the short run, patients who are good remyelinators may do almost as well without treatment as with it. 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, Dr. Erickson and his team are developing ever more refined, innovative techniques to identify evidence of remyelination in brain-imaging studies.

There also may be genetic factors involved in the natural ability to remyelinate successfully. Dr. Lucchinetti is leading a study funded by the National Institutes of Health to investigate gene-based differences among good and poor remyelinators. If genetic factors emerge, the goal would be to create gene-modifying therapies to promote strong remyelination.

What's the Potential Impact?

Multiple sclerosis affects one in every 1000 people in the Western world. Mayo Clinic Rochester alone sees over 1,500 new cases of MS a year. And it is one of the most common causes of disability in young adults.

Aware of the challenges ahead, Dr. Lucchinetti sees saving axons as one of the best means of preventing intractable disability in patients who "get worse, despite therapies that impact the early-stage inflammatory aspect of the disease." If successful, Dr. Rodriguez anticipates that autoantibody Number 22, and other naturally occurring antibodies they have discovered, may lead toward therapeutic nervous system repair not only in MS but also potentially in other neurodegenerative diseases and spinal cord injury.

For more about MS, visit mayoclinic.com, for treatment options visit mayoclinic.org.

- Penelope Duffy, Ph.D.