Editors' ChoiceRegenerative Medicine

A Pillar of Hope for New Multiple Sclerosis Therapeutics

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Science Translational Medicine  30 Jul 2014:
Vol. 6, Issue 247, pp. 247ec132
DOI: 10.1126/scitranslmed.3009822

Multiple sclerosis (MS) is the most common chronic neurological disease among young adults. MS is thought to result from an autoimmune-mediated attack of myelin-producing cells called oligodendrocytes in the central nervous system (CNS). Current therapies for MS include at least 10 anti-inflammatory drugs that have been approved by the U.S. Food and Drug Administration. Many of these drugs show substantial disease-modifying activity for patients by modulating the inflammatory components of the disease. However, none of these current drugs promote regeneration of lost myelin in the CNS, and therefore they are largely ineffective at preventing disease progression and ultimately disability. Now, using an innovative high-throughput screening assay, Mei et al. offer a new approach to discover drugs that may directly enhance remyelination in diseases such as MS.

In this new study, the authors describe the design, fabrication, and implementation of a screening platform called BIMA (binary indicant for myelination using micropillar assays). During the process of myelination in the CNS, oligodendrocyte progenitor cells (OPCs) mature into oligodendrocytes, which physically wrap around neurons to create the myelin sheath. The authors had previously shown that oligodendrocytes will even wrap around pseudo-neuronal substrates in vitro. They leveraged this key finding to engineer arrays of compressed silica micropillars that could be incorporated into cell culture microplates. Upon addition of rodent OPCs, ~10% of the cells would wrap around the micropillars, and this could be quantified in an automated fashion by staining for “rings” of myelin markers such as myelin basic protein (MBP). The authors’ major advance was their ability to test a 1000-drug library in their assay in order to evaluate whether the extent of micropillar wrapping could be enhanced. They identified a cluster of eight antimuscarinic drugs, which have previously been approved for use in other diseases. The authors functionally validate one of these drugs, clemastine, in an in vivo rodent remyelination assay.

The ability to enhance remyelination is a major unmet clinical need. New screening platforms such as the one in this paper provide a mechanism to identify promising candidates for clinical testing in MS and other myelin disorders. Given its oral bioavailability and known safety profile, clemastine is currently being tested in a phase II clinical trial for MS. However, the ability to accurately measure remyelination is not currently feasible in the context of a clinical trial, and major advances must be made in order to accurately test the plethora of remyelinating therapeutics that are likely to emerge in the near future.

F. Mei et al., Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 10.1038/nm.3618 (2014). [Full Text]

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