Better Understanding of Remyelination Pathway Offers Promise for New Multiple Sclerosis Treatments

Real hope for modifying the disease course of multiple sclerosis (MS) may come from strategies to remyelinate damaged neurons and brain cells, says Catherine Lubetzki, MD, of the Pierre and Marie Curie University and Pitie-Salpetriere Hospital in Paris, France. Speaking on April 30, 2014, at the American Academy of Neurology’s 2014 annual conference in Philadelphia, PA, Lubetzki mapped out the pathway her lab is building from basic science to drug development for new MS agents.

She told the audience that treatments effectively targeting the inflammatory component of MS are still lacking. Pilot and phase 2 studies are underway with agents aimed at reducing inflammation, enhancing neuroprotection, and encouraging remyelination; however, the remyelination pathway in particular has not been well understood. Currently, the SPRINT-MS study for ibudilast in relapsing-remitting and primary progressive MS is underway with 250 patients planned to enroll. The phase 2 MS-SMART study of secondary progressive MS will enroll 440 patients in one of four treatment arms to receive riluzole, amiloride, ibudilast, or placebo.

Even given the current and emergent treatment landscape, remyelination, when it does occur, is insufficient to overcome chronic axonal damage and resultant disease progression. To understand why remyelination fails, the processes involved in oligodendrocyte precursor cell (OPC) activity must be made clear. These cells, which migrate to areas of plaque, mature, and eventually wrap around axons to remyelinate, do so through a four-step process. First, the cells are activated; then, they are recruited to migrate. Next, they achieve maturation before finally completing their wrap and myelination of the axon.

Lubetzki’s lab has used a mouse model to examine the transition from quiescent to activated OPCs, and to achieve a better understanding of the transcription profile of mature OPCs. Her group’s work shows that demyelination-induced activation of adult OPCs makes the cells revert to a less mature gene cell, providing cues to promote OPC motility, necessary for activation and recruitment of these cells to the demyelinated areas with plaque burden.

OPCs must then receive guidance for targeted migration to demyelinated areas. Two genes have been identified which seem to have opposing effects on OPC recruitment and remyelination rates. Overexpression of the Sema 3F gene has been associated with increased OPC recruitment and with increased remyelination rates, while overexpression of netrin has the opposite effect, decreasing OPC recruitment and reducing the rate of remyelination. Thus, a primary focus is to target Sema 3F at the lesion site, increasing the rate of remyelination by increased (and targeted) OPC recruitment. Critically, this must be accomplished early in the disease process, when axonal damage may still be reversible.

Lingo-1 has also been identified as a down-regulator of OPC activation and recruitment; researchers are also attempting to achieve early remyelination through use of an anti Lingo-1 monoclonal antibody. Two trials are currently underway examining this drug. The SYNERGY trial plans to follow 400 patients with relapsing-remitting MS over 18 months, while the RENEW trial for sufferers of optic neuritis (another inflammatory demyelinating disorder) will examine the drug’s effects on 80 patients over six months.

Fielding questions from the overflow crowd following the presentation, Lubetzski discussed the outcome measures under consideration to measure efficacy of these drugs in humans. In addition to using magnetic resonance imaging to show remyelination and to follow brain atrophy, positron emission tomography using a myelin ligand may become clinically useful. However, she also emphasized the primacy of maintaining a patient-centered focus, and the critical importance of paying attention to improvement in clinical endpoints.