Two drugs used to treat non-MS conditions promote myelin repair in mice
Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) in which myelin – the coating that surrounds nerve fibers and is produced by oligodendrocytes – is attacked and damaged by the immune system. Myelin repair (or remyelination) is carried out by a group of cells called oligodendrocyte progenitor cells (OPCs for short). Following an attack, OPCs are activated and mature into myelin-producing oligodendrocytes, reapplying myelin to damaged areas. However, this process often fails in MS, leading to accumulating myelin damage and, over time, a chronic progressive form of the disease. Current MS treatments, while effective at limiting myelin damage, cannot stop or reverse remyelination failure.
A team of researchers led by Dr. Paul J. Tesar performed an extensive drug screen to identify and then repurpose clinically tested drugs as remyelinating therapeutics. Their goal: to kick-start OPC production of myelin-forming cells. Their findings appear in the journal Nature.
727 drugs were chosen for study. The drugs had a proven safety record in humans, and were picked from the US National Institutes of Health (NIH) Clinical Collections I and II libraries. Researchers developed a new cell-culture based screening protocol to narrow down the list of drugs to those that drove mouse OPCs to become mature, myelin-producing oligodendrocytes. Drugs that increased the generation of mature cells were passed through a second screen to determine their remyelination potential in cultured CNS tissue.
Drugs with the highest impact on myelination were administered to mice with toxin-induced demyelination. The researchers then determined how each drug affected the number of mature oligodendrocytes and the relative number of remyelinated nerve fibers.
Drugs were also administered to mice with two different forms of an MS-like disease; an immune-driven relapsing-remitting form and a chronic progressive one. The immune-driven form was used to demonstrate how the drugs affected immune cell survival and function, along with disease severity. The purpose of the chronic progressive model, on the other hand, was to see if the drugs could reverse (rather than simply prevent) disability when given to mice with ongoing chronic disease.
The researchers also used cell culture experiments to test the ability of selected drugs to provoke OPCs derived from humans to mature into myelin-forming oligodendrocytes.
Of the 727 screened, two drugs showed significant potential and were chosen for study in mice: miconazole, a topical antifungal, and clobetasol; a topical corticosteroid. Both drugs increased mature oligodendrocyte number and enhanced remyelination capacity in mice with damaged myelin.
Only clobetasol reduced disease severity in mice with the immune-driven relapsing-remitting disorder due to its immunosuppressive effects. However, in mice with the chronic progressive form, both miconazole and clobetasol reversed disability (animals regained use of their hind limbs) and reduced spinal cord demyelination when administered after disease onset. Based on their findings, the researchers suggest that clobetasol acts both as an immune modifying and remyelinating drug, while miconazole acts as a remyelinating drug only.
Finally, the researchers demonstrated that both drugs enhanced the generation of mature myelin-producing oligodendrocytes from human OPCs in cell culture, suggesting that these promising preclinical results have the potential to be translated to people living with MS.
The research team conducted drug screening on an impressive scale, identifying two therapeutic candidates for MS – miconazole and clobetasol – with demonstrated safety records in clinical trials. The drugs were shown to enhance the production of mature oligodendrocytes, promote remyelination of nerve fibers and reduce severity of MS-like disease symptoms in mice.
It is significant and encouraging that, through innovative techniques, researchers have been able to quickly identify drugs with the potential to repair myelin. As there is currently no treatment for the progressive form of MS in humans, the ability of these drugs to reduce disease severity in mice with a progressive MS-like disease points to a promising therapeutic. However, as miconazole and clobetasol are currently approved for topical use only, dosing, delivery, and drug formulation will need to be thoroughly tested to maximize efficacy and minimize potential side effects. Nonetheless, the researchers suggest that, with more study, either drug may be a future therapeutic candidate for MS.
Najm FJ et al. (2015). Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature. Epub ahead of print doi:10.1038/nature14335