Promoting myelin repair and return of function in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Conduction block in demyelinated axons underlies early neurological symptoms, but axonal transection and neuronal loss are believed to be responsible for more permanent chronic deficits. Several therapies are approved for treatment of relapsing-remitting MS, all of which are immunoregulatory and clinically proven to reduce the rate of lesion formation and exacerbation. However, existing approaches are only partially effective in preventing the onset of disability in MS patients, and novel treatments to protect myelin-producing oligodendrocytes and enhance myelin repair may improve long-term outcomes. Studies in vivo in genetically modified mice have assisted in the characterization of mechanisms underlying the generation of neuropathology in MS patients, and have identified potential avenues for oligodendrocyte protection and myelin repair. However, no treatments are yet approved that target these areas directly, and in addition, the relationship between demyelination and axonal transection in the lesions of the disease remains unclear. Here, we review translational research targeting oligodendrocyte protection and myelin repair in models of autoimmune demyelination, and their potential relevance as therapies in MS.

Figure 1. Regulation of oligodendrocyte progenitor mitosis, differentiation and apoptosis

An outline of the progression of oligodendrocyte differentiation, from neural progenitor (left), through specified oligodendrocyte progenitor, to mature postmitotic oligodendrocyte capable of myelin formation (right). Mechanisms of action are shown of factors that augment (lower panel, blue/green) or restrict (upper panel, red) the number of mature myelinating cells. Retinoid X receptor signaling and the gp130 cytokines CNTF, IL-11 and LIF promote oligodendrocyte maturation (lower panel). The gp130 cytokines also improve the viability of mature oligodendrocytes or their precursors, a property they share with the insulin-like growth factors IGF-1 and IGF-2, and the neurotrophin, NT-3. Additionally, NT-3 potentiates precursor proliferation. At later stages of maturation, neuregulin 1 type III-ErbB signaling facilitates axonal ensheathment and myelin wrapping. Conversely, bone morphogenetic proteins inhibit oligodendrocyte lineage specification and subsequent progenitor differentiation (upper panel). Canonical Notch and Wnt signaling restrict maturation, and maintain the size of the progenitor pool.