Regenerating CNS myelin — from mechanisms to experimental medicines

Key Points Remyelination is a spontaneous regenerative process in the adult mammalian CNS in which new oligodendrocytes and myelin sheaths are generated from a widespread population of adult progenitor cells. Remyelination involves the distinct stages of progenitor activation, recruitment (proliferation and migration) and differentiation into mature myelin-sheath-forming oligodendrocytes: each is orchestrated by a complex network of cells and signalling molecules. The efficiency of remyelination declines progressively with adult ageing, a phenomenon that has a profound bearing on the natural history of chronic demyelinating diseases such as multiple sclerosis, although experimental studies have revealed that the effects of age are reversible. Remyelination is neuroprotective, limiting the axonal degeneration that follows demyelination. Restoring remyelination is therefore an important therapeutic goal so as to prevent neurodegeneration and progressive disability in multiple sclerosis and other myelin diseases. Insights into the mechanism governing remyelination and an increasing number of high-throughput screening platforms have led to the identification of a number of drug targets for the pharmacological enhancement of remyelination, some of which have entered clinical trials. Advances in the generation of large numbers of human stem and progenitor cells, coupled with compelling preclinical data, have opened up new opportunities for cell-based remyelination therapies, especially for the leucodystrophies. Promoting remyelination may be an effective therapeutic strategy for various disorders that are characterized by a loss of myelin, including multiple sclerosis. In this Review, Franklin and ffrench-Constant discuss recent developments in our understanding of remyelination and the efforts that are underway to enhance this process. Although the core concept of remyelination — based on the activation, migration, proliferation and differentiation of CNS progenitors — has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutica