Remyelination

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Petr75
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Remyelination

Post by Petr75 » Mon Feb 25, 2019 12:06 pm

2019 Jan 29
Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE), Department of Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, ETH Zurich, 8057 Zurich, Switzerland
Remyelination promoting therapies in multiple sclerosis animal models: a systematic review and meta-analysis.
PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351564/

Abstract
An unmet but urgent medical need is the development of myelin repair promoting therapies for Multiple Sclerosis (MS). Many such therapies have been pre-clinically tested using different models of toxic demyelination such as cuprizone, ethidium bromide, or lysolecithin and some of the therapies already entered clinical trials. However, keeping track on all these possible new therapies and their efficacy has become difficult with the increasing number of studies. In this study, we aimed at summarizing the current evidence on such therapies through a systematic review and at providing an estimate of the effects of tested interventions by a meta-analysis. We show that 88 different therapies have been pre-clinically tested for remyelination. 25 of them (28%) entered clinical trials. Our meta-analysis also identifies 16 promising therapies which did not enter a clinical trial for MS so far, among them Pigment epithelium-derived factor, Plateled derived growth factor, and Tocopherol derivate TFA-12.We also show that failure in bench to bedside translation from certain therapies may in part be attributable to poor study quality. By addressing these problems, clinical translation might be smoother and possibly animal numbers could be reduced.








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Petr75
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Re: Remyelination

Post by Petr75 » Tue Feb 26, 2019 12:15 pm

2019 Jan 29
University of California, San Francisco, Weill Institute for Neurosciences, Department of Neurology.
Inception Sciences, San Diego
Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors.
https://www.ncbi.nlm.nih.gov/pubmed/30696729

Abstract
A significant unmet need for patients with multiple sclerosis (MS) is the lack of FDA-approved remyelinating therapies. To this end, we have identified a compelling remyelinating agent, Bazedoxifene (BZA), an EMA-approved (and FDA-approved in combination with conjugated estrogens) selective estrogen receptor modulator (SERM) that could move quickly from bench to bedside. This therapy stands out as a tolerable alternative to previously identified remyelinating agents, or other candidates within this family. Using an unbiased high-throughput screen, with subsequent validation in both murine and human oligodendrocyte precursor cells (OPCs), as well as co-culture systems, we find that BZA enhances differentiation of OPCs into functional oligodendrocytes. Using an in vivo murine model of focal demyelination, we find that BZA enhances OPC differentiation and remyelination. Of critical importance, we find that BZA acts independent of its presumed target, the estrogen receptor, in both in vitro and in vivo systems. Employing a massive computational data integration approach, we independently identify 6 possible candidate targets through which SERMs may mediate their effect on remyelination. Of particular interest, we identify EBP (encoding 3β-hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis pathway, which was previously implicated as a target for remyelination. These findings provide valuable insights into the implications for SERMs in remyelination for MS and hormonal research at large.SIGNIFICANCE STATEMENTTherapeutics targeted at remyelination failure, which results in axonal degeneration and ultimately disease progression, represents a large unmet need in the multiple sclerosis (MS) population. Here, we have validated a tolerable EMA-approved (FDA-approved in combination with conjugated estrogens) selective estrogen receptor modulator (SERM), Bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) differentiation and remyelination. SERMs, developed as nuclear estrogen receptor (ER) α and β agonists/antagonists, have previously been implicated in remyelination and neuroprotection, following a heavy focus on estrogens with underwhelming and conflicting results. We show that nuclear ERs are not required for SERMs to mediate their potent effects on OPC differentiation and remyelination in vivo, and highlight EBP, an enzyme in the cholesterol biosynthesis pathway, that could potentially act as a target for SERMs.

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