Promoting repair in multiple sclerosis: problems and prospects.
OBJECTIVE
Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy.


RESULTS
Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels.


CONCLUSIONS
Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.
Lubetzki
Catherine
C
Fédération de Neurologie, Hôpital de la Salpêtrière, Université Pierre et Marie Curie, Paris, France. catherine.lubetzki@psl.ap-hop-paris.fr
Williams
Anna
A
Stankoff
Bruno
B
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000150:complications / Q000628:therapy*; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000150:complications / Q000628:therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D014945:Wound Healing
D007155:Immunologic Factors; D018696:Neuroprotective Agents