Basic science projects
Over the last twenty years, the Rodriguez laboratory has identified a series of monoclonal antibodies that enhance remyelination in animal models of MS (supported by NIH R01 NS24180). These include a viral model (Theiler's virus-induced demyelination), a toxic model (lysolecithin-induced demyelination), and an autoimmune model (experimental autoimmune encephalomyelitis induced by MOG protein).
The goal of these studies is to determine how antibodies promote new synthesis of myelin and CNS repair. Antibodies identified to date bind to the surface of oligodendrocytes and to lipids or gangliosides in membranous lipid rafts to trigger a signaling cascade instructing the oligodendrocytes to myelinate. (Under the MS Center grant CA1011)
The short-term goal is to define the signaling pathways that induce myelination and remyelination. This information is essential for designing small molecules with potential to stimulate myelin repair by acting on this signaling pathway. Development of assays to monitor beneficial manipulation of the signaling pathway, in collaboration with pharmaceutical companies, will allow rapid screening of >100,000 compounds for their potential to enhance myelin repair. The project is funded by grants from National Institutes of Health (R01 NS24180) and the National Multiple Sclerosis Society (RG 3172).
The Rodriguez laboratory (in collaboration with the Pease laboratory) has generated several human monoclonal antibodies that induce CNS repair. The antibody in most advanced development, designated recombinant IgM 22, has been fully characterized at the molecular level and has been genetically engineered for mass production in a GMP facility at the University of Minnesota. The GMP-produced antibody induces remarkable remyelination without toxic side effects animals with experimentally induced demyelination (work in collaboration with Dr. Ron Marler, Scottsdale, AZ). A planned Phase I/Phase II clinical trial, awaiting approval from the FDA, will evaluate CNS myelin repair in patients with moderate-to-severe neurological deficits from MS. Dr. Warrington, who originally identified IgM22, helped Dr. Rodriguez prepare the IND application for the FDA. This project is funded by a grant from the Hilton Foundation. Dr. Basford's Rehabilitation Training Grant (NIH HD07447) has supported the salaries of postdoctoral fellows in this field of research.
Update: Remyelination Clinical Trial
Mayo Clinic and Acorda Therapeutics, Inc. have been working together for more than ten years to explore the potential use of rHIgM22 (also known as Antibody 22) in multiple sclerosis (MS). In January 2013, the FDA gave its approval for a Phase 1 clinical trial enrolling people with MS to assess the safety and tolerability of rHIgM22. The study also includes several exploratory efficacy measures.
In preclinical studies, rHIgM22 has been shown to stimulate production of new myelin and improve function. It is the first drug that seeks to address the loss of myelin that can cause progressive functional impairment in people with MS.
The primary objective of this double-blind, randomized single ascending dose study is to evaluate the safety and tolerability of rHIgM22 in people with MS. The study also includes several exploratory efficacy measures, including magnetic resonance imaging and standard clinical measures used to assess people with MS, such as walking ability. Participants in the trial will receive either placebo or rHIgM22 administered as a single intravenous dose. If rHIgM22 is well tolerated in study groups receiving a low dose of rHIgM22, subsequent groups will receive single infusions of higher doses. Participants in this study will continue receiving their standard MS treatments.
Additional details on this clinical study, including enrollment criteria and contact information for study sites, can be found at: http://www.clinicaltrials.gov/ct2/show/NCT01803867?term=acorda&rank=12
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