Strategies to promote remyelination
Our lab's main goal is to discover new ways to promote remyelination in the central nervous system, while also developing aptamers and broad-spectrum antiviral agents.
The Multiple Sclerosis Laboratory of Moses Rodriguez, M.D., at Mayo Clinic focuses on determining the mechanisms of demyelination and remyelination in diseases such as multiple sclerosis (MS) through primary animal models of demyelination. Working with Dr. Rodriguez in the Multiple Sclerosis Lab is Arthur E. Warrington Jr., Ph.D., an assistant professor of neurology and neurosurgery at Mayo Clinic College of Medicine and Science in Rochester, Minnesota.
The Multiple Sclerosis Lab is particularly interested in developing strategies to promote remyelination in the central nervous system.
Having observed that immunization of Theiler's virus-infected mice with spinal cord homogenate induces remyelination, Dr. Rodriguez and his research team subsequently showed that transfer of immunoglobulins directed against the spinal cord into animals chronically infected with Theiler's virus induces remyelination.
As a result, our lab generated a series of mouse monoclonal antibodies that promotes remyelination. These antibodies are directed against surface components on oligodendrocytes. They proved to be natural autoantibodies with germline DNA sequences.
Our lab has generated two human monoclonal antibodies that also bind to the surface of rat and human oligodendrocytes and that promote remyelination in both the Theiler's virus system and the lysolecithin model system. Recombinant antibody has been generated that shows similar promotion of remyelination as the serum antibodies.
After extensive toxicology testing, one of the antibodies (rHIgM22) completed phase I clinical trials. These natural human autoantibodies against oligodendrocytes proved to have no toxicity in 72 patients with fixed neurological deficits in multiple sclerosis. In addition, the antibody was seen in the cerebrospinal fluid of all patients tested, indicating that these large molecules do cross the blood-brain barrier. A second trial in 30 patients with acute attacks of MS also was found to be safe. Data from the efficacy of this trial have not yet been released from Acorda Therapeutics, which owns the license for this antibody. Phase II clinical trials with rHIgM22 are being planned.
Our lab has generated a new antibody (rHIgM12) that is directed at neurons and axons rather than at oligodendrocytes and that has shown remarkable efficacy in the progressive forms of demyelination characterized by extensive axonal injury. In addition, this antibody has increased the life span of animals with the genetic SOD1 forms of amyotrophic lateral sclerosis (ALS).
Experiments are also underway to determine whether any of the antibodies are effective in animal models of acute spinal cord injury or in conditions of neonatal hypoxia at birth to prevent cerebral palsy.
Aptamers are drugs made from unique sequences of DNA or RNA that bind specifically to cell or protein targets. Our lab, in collaboration with Dr. Warrington and Mayo Clinic researcher Louis J. (Jim) Maher III, Ph.D., has identified a sequence of DNA that binds specifically to myelin.
Experiments showed that when this sequence of DNA is combined to form an avidin-biotin complex that mimics an antibody, this complex (termed Myaptavin-3064), made up of 40 nucleotides, promotes new myelin formation in animals with multiple sclerosis-like diseases. A smaller molecule of 20 nucleotides appears to also promote repair. These molecules are much cheaper to make than antibodies and seem to cross the blood-brain barrier with greater ease. We are looking for partners for clinical development.
Our lab is also developing broad-spectrum antiviral agents. Researchers in our lab have discovered that transgenic mice expressing the RNA-dependent RNA polymerase of Theiler's virus are resistant to a wide group of both RNA and DNA viruses. The reason for the resistance is that the mice mount a class I interferon response where more than 100 genes controlling virus defense are up-regulated.
Work is underway to determine ways to use this observation to generate a new line of drugs that could be useful to fight bioterrorism or serious viral epidemics.
About Dr. Rodriguez
Dr. Rodriguez, a specialist in neuroregeneration at Mayo Clinic in Rochester, Minnesota, is a nationally recognized multiple sclerosis expert who conducts scientific research and treats patients. He has published hundreds of scientific articles about his research findings on MS and related conditions.