Immune Promotion of Remyelination Optimization of Antibody Enhanced Remyelination
These are two projects that complement and enhance each other and are funded by the NIH and NMSS respectively.
The goal is to develop strategies to promote remyelination in the central nervous system. Experiments are designed to use "knockout" mice with specific immune deletions as well as to test monoclonal antibodies to enhance remyelination. We have identified a series of human monoclonal antibodies that bind to the surface of oligodendrocytes (view image). These antibodies trigger remyelination both in vivo and in vitro (view image). Antibodies have been shown to promote remyelination and functional improvement in three experimental models of multiple sclerosis (viral, autoimmune and toxic). Two monoclonal antibodies have been cloned and the sequence expressed in vectors so that large amounts of antibody can be readily made. MRI studies show that these antibodies cross the blood brain barrier (view image) and target the MS lesion. These antibodies are expressed at a specific time in glial cell development and bind specifically to myelin.
We have presented this work to the FDA and have overseen the generation of antibodies in an FDA-approved facility. Upon completion of final toxicology, we will initiate Phase I-II clinical trials. This will be the first attempt to enhance remyelination in patients with multiple sclerosis. Because it uses natural human monoclonal antibodies, this approach is expected to be safely applicable to a large number of patients.
We (specifically Drs. Bieber and Rodriguez) have collaborated to demonstrate that T cells are necessary for remyelination to take place . We have also begun to explore the genetic basis of remyelination . The mouse strain FVB has been found to repair spontaneously while others (B10.Q and SJL) do not. Most recently, using NMR technology, we have been able to develop a surrogate marker for axonal preservation by examining the ratio of NAA/cr by spectroscopy.
The concept of antibodies repairing the central nervous system may have wider applications. Antibodies have been discovered that promote the extension of axons in culture. These have relevance to the treatment of spinal cord injury, stroke and Alzheimer's disease.