Information travels through the brain as electrical messages from one nerve cell (neuron) to another in a series of connections (pathways) that control various functions (i.e. motor control of walking and cognitive control of short term memory). Similar to an electrical wire, the processes (neuronal axons) that carry the information are insulated which controls strength and speed of conduction. The insulation is called myelin (consisting of lipids and protein) and is produced by surrounding cells called oligodendrocytes that physically concentrically wrap their extensions around axons. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system characterized by break down of myelin (demyelination) and axons (neurodegeneration). This can slow or stop messages. Currently available disease modifying therapies, for reduction of frequency and severity of relapses, are global immunosuppressants acting through non-specific inhibition of immune cell (i.e. T-cell) activation/function and/or trafficking into the brain. These FDA-approved drugs have limited efficiency and are often associated with serious side effects. The Miller Lab has developed a novel method of inducing immune tolerance to selectively suppress known immune responses without compromising the entire adaptive immune system (i.e. ability to fight infection). There are millions of "flavors" of receptors on immune cells that can recognize different substances (antigens) that provoke an immune response. In MS the antigens are myelin proteins. The Miller lab has recently demonstrated effective means of alleviating disease in a mouse model of MS through tolerance induction using biodegradable PLG nanoparticles encapsulating myelin antigens (Ag-PLG). This works to prevent disease induction, but more importantly can stop disease progression in mice treated during the remission period following the initial clinical episode resulting in antigen-specific blockade of disease relapses. Today, there are no FDA-approved therapies for enhancing myelination despite successful in vitro and in vivo pre-clinical testing of several molecules/compounds reported to promote oligodendrocyte differentiation/maturation. As autoimmunity and neurodegeneration underlie MS, effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. This research will test the hypothesis that remyelination can be more efficiently induced in mice in which the underlying autoimmune response is specifically regulated. The research project will involve examining the effects of therapies employing drugs which promote myelin repair by stimulating oligodendrocyte progenitor cell expansion to create new cells for repair, homing to areas of damage and/or differentiation to produce myelin combined with nanoparticle tolerance-based immunoregulatory therapies on T cell-mediated EAE mouse models of Multiple Sclerosis. The proposed pre-clinical trials may provide a novel and safe targeted approach that can be translated into effective disease modifying therapies for MS patients. The results from these studies may not only prove a rapid and safe therapeutic strategy for EAE reversal, but will also pave the way for future clinical studies in MS undertaking this combinatorial therapeutic approach.
|Effective start/end date||7/1/15 → 6/30/18|
- National Multiple Sclerosis Society (FG 20125-A-1)