Current advancements in promoting remyelination in multiple sclerosis

Abstract

Current multiple sclerosis (MS) therapies are effective in reducing the rate of relapse, short-term measures of disability, and MRI measures of inflammation, whereas in progressive/degenerative disease phases, these medications are of little or no benefit. Therefore, the development of new therapies aimed at reversing neurodegeneration is of great interest. Remyelination, which is usually a spontaneous endogenous process, is achieved when myelin-producing oligodendrocytes are generated from oligodendrocyte precursor cells. Even though these precursor cells are abundant in MS brains, their regeneration capacity is limited. Enhancing the generation of myelin-producing cells is therefore a major focus of MS research. Here we present an overview of the different advancements in the field of remyelination, including suitable animal models for testing remyelination therapies, approved medications with a proposed role in regeneration, myelin repair treatments under investigation in clinical trials, as well as future therapeutics aimed at facilitating myelin repair.

Human retrovirus pHEV-W envelope protein and the pathogenesis of multiple sclerosis

“…Given the molecular weight of humanized anti-ENV monoclonal antibody, GNbAC1, an IgG4, one might argue it is likely that the protective effects on MRI shown in the phase IIb study are mediated by inhibition of peripheral blood cells expressing the hHERV-W protein rather than by significant concentrations in the CNS, particularly in lesions with modest deficits in the integrity of the blood brain barrier. Similar beneficial effects on MRI metrics have been reported with many other treatments for MS (37) with agents that are predominately if not exclusively antiinflammatory, many unlikely to be directly effective in the CNS (large proteins) and none having any known specificity for any viral proteins. Increased expression of the HERV-Fc-1 locus Gag RNA for HERV-W in plasma after a relapse and poorer prognosis with higher levels of the protein in the peripheral immune system argues for peripheral effects, as does the reduction of expression of MSRV/synctin-1/HERV-W in blood cells in response to chronic administration of natalizumab, a monoclonal antibody directed against α-4 integrin which inhibits entry of inflammatory cells into the CNS (38).…”

Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses

“…4d), again suggesting that WFS1 is implicated in development and preferentially expressed in glia including oligodendrocytes. Gene ontology (GO) analysis of this 4 month-4 year WFS1 -related gene set using BiNGO, a biological network gene ontology tool (https://www.psb.ugent.be/cbd/papers/BiNGO/Home.html) [74], and the EBI Gene Ontology Annotation Database (2019-03-18 release) [75, 76], also recovered oligodendrocyte- and glia-related terms such as oligodendrocyte differentiation, axon ensheathment, ensheathment of neurons, myelination, gliogenesis, glial cell differentiation, oligodendrocyte development, and glial cell development which were within the top 10 most statistically overrepresented biological processes at this age ( p < 9E-11, FDR corrected, Additional file 3). Taken together, these gene expression data suggest a role for WFS1 in myelination by the gene’s co-expression with transcripts characteristic of these cell types and by the gene’s peak expression during developmental periods related to glial maturation.…”

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

“…Adjusting glia cell-fate imbalance, hence overcoming intrinsic defects in oligodendroglial cell maturation and subsequently developmental dysmyelination, will be a major target in order to improve white matter structures in DS. To this end, repurposing pre-existing modulators or compounds developed for the promotion of endogenous oligodendroglial cell maturation in demyelinating diseases such as multiple sclerosis (MS) [9,[124][125][126] represents a possible strategy. In this context, currently evaluated drugs related to the development of myelin-repair therapies are discussed here.…”