The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment

Abstract

Within CNS disorders, demyelinating diseases are among the most devastating and cost intensive due to long-term disabilities affecting relatively young patients. Multiple sclerosis, a chronic inflammatory demyelinating disease in which the persistent inhibitory microenvironment of the resident oligodendrocyte precursor cells abrogates regeneration of myelin sheaths, is the most prominent disease in the spectrum of demyelinating diseases. The essential goal is to stimulate creation of new myelin sheaths on the demyelinated axons, leading to restoration of saltatory conduction and resolving functional deficits. The past few decades witnessed significant efforts to understand the cellular interactions at the lesion site with studies suggesting efficient remyelination as a prerequisite for functional repair. Despite its proven efficacy in experimental models, immunosuppression has not had profound clinical consequences in multiple sclerosis, which argued for a paradigm shift in the design of therapeutics aiming to achieve remyelination. For example, targeting oligodendrocytes themselves may drive remyelination in the CNS. This group and others have demonstrated that natural autoreactive antibodies directed at oligodendrocyte progenitors participate in remyelination. Accordingly, the authors developed a recombinant autoreactive natural human IgM antibody with therapeutic potential for remyelination.