Myelin Repair in Multiple Sclerosis
In the healthy central nervous system (CNS), myelin allows for the propagation of electrical impulses, while providing protection and metabolic support for nerve cells. Demyelination, the pathological damage or loss of myelin, is a hallmark of multiple sclerosis (MS), an autoimmune disease mediated by immune cell attacks against the CNS.
Myelin Repair Research
Although therapies have been developed to modulate the immune response in MS, myelin repair therapies are not yet a reality. Several potential strategies to enhance remyelination are under investigation, including small molecules, small interfering RNAs, and monoclonal antibodies that target specific components of the signaling pathways that underlie myelination.
The neurite outgrowth inhibitor Nogo-A plays a role in blocking remyelination. Because impaired remyelination is a pathological hallmark of MS, neutralization of Nogo-A has potential application in achieving myelin repair in multiple sclerosis. Several Phase 1 studies with anti-Nogo-A antibodies have been conducted in MS with a relapsing remitting course (NCT01424423, NCT01435993). Both studies were terminated and results are not published yet. Reasons for termination were unrelated to safety issues of the antibody treatment.
An antibody against a Nogo receptor subunit, LINGO-1, improved outcomes in patients with acute optic neuritis in a Phase 2 study (NCT01721161). However, initial results have failed to show significant therapeutic outcomes in MS patients. Two randomized, double-blind, placebo-controlled clinical trials to evaluate safety, tolerability, pharmacokinetic profile, and efficacy of an anti-LINGO-1 monoclonal antibody in MS have been completed (NCT01864148, NCT01244139).
Vitamin D is thought to play a protective role in autoimmune diseases. In this context, numerous studies have investigated the role of vitamin D in MS. Beneficial effects of vitamin D supplementation that have been reported included decreases in disability and MRI lesions, increased functionality, and reduced relapse rates. Meanwhile, two other trials reported no difference in these parameters.
MD1003 is an oral formulation of a highly concentrated form of vitamin, which has shown promising results in progressive MS in a pilot open-label study. A randomized, double blind, placebo controlled study showed that MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well-tolerated. A Phase 3 trial is underway (NCT02936037).
High-throughput drug screening has been used to screen drugs for myelinating potential. Two drugs, miconazole and clobetasol, were identified from an NIH drug library and found to enhance remyelination in animal models. Additionally, these assays have utility in identifying compounds that promote the differentiation of oligodendrocyte precursor cells into myelin-producing oligodendrocytes.
A human monoclonal antibody, sHIgM22, was found to promote remyelination in animal models. A Phase 1, multi-center, double-blind, randomized, placebo-controlled study was conducted in MS using a recombinant antibody, rHIgM22 (NCT01803867). A second Phase 1 trial has begun enrollment to assess the safety and tolerability of rHIgM22 following a relapse (NCT02398461).
Semaphorin 4D signaling inhibits remyelination and axonal regeneration. An antibody that inhibits semaphorin, VX15/2503, is being tested to determine whether it promotes remyelination. VX15/2503 has been evaluated in a Phase 1, double-blind, placebo-controlled study in MS (NCT01764737) of ascending single doses of intravenous VX15/2503. VX15/2503 was well-tolerated at dose levels of up to 20 mg/kg without treatment-related serious adverse events.
Retinoid X receptor gamma appears to promote myelin repair in multiple sclerosis. Drugs such as bexarotene (Targretin) that target this molecule are expected to be evaluated for chronic MS.