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.
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.
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.
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.
Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases.
The mechanisms regulating differentiation of multipotent oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs) are critical to our understanding of myelination and remyelination. Following acute demyelination in the central nervous system, adult OPCs migrate to the injury site, differentiate into OLs and generate new myelin sheaths. A common feature of regenerative processes is the fact that remyelination efficiency declines with aging and, accounts for the observation that chronic demyelinating diseases like multiple sclerosis (MS) are characterized by an ineffective remyelination. Without doubt, impairment of OPC differentiation is an essential determinant of the aging effects in remyelination. However, spontaneous remyelination is limited in demyelinating diseases such as MS, owing in part to the failure of adult OPCs to differentiate into myelinating OLs. The inability to restore myelin after injury compromises axon integrity and renders them vulnerable to degeneration. Although the genes that regulate the proliferation and differentiation of OPCs during development have been intensively studied, relatively little is known about the molecular signals that regulate the function of adult OPCs after demyelination. Elucidating the mechanisms regulating OPC differentiation are key to identifying pharmacological targets for remyelination-enhancing therapy. This review will discuss OPC biology, myelination, and possible pharmacological targets for promoting the differentiation of OPCs as a strategy to enhance remyelination, including the potential for nanoscale delivery.
Department of Physiology & Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland
Myelin repair stimulated by CNS-selective thyroid hormone action
Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.
Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, China
Small Molecules with Big Promises for Curing Demyelinating Diseases
Myelin regeneration by myelinating oligodendrocytes is key to neuronal damage repair for treatment of neurological disorders such as multiple sclerosis. In this issue of Cell Chemical Biology, Allimuthu et al. (2019) report new small molecule inhibitors of cholesterol biosynthesis enzymes that enhance oligodendrocyte formation and subsequent remyelination.
Here's the abstract of the paper that letter discusses.
Diverse Chemical Scaffolds Enhance Oligodendrocyte Formation by Inhibiting CYP51, TM7SF2, or EBP.
Cell Chem Biol. 2019 Apr 18;26(4):593-599.
- Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules. Identification of the cellular targets of these validated hits revealed a majority inhibited the cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP. In addition, evaluation of analogs led to identification of CW3388, a potent EBP-inhibiting enhancer of oligodendrocyte formation poised for further optimization.
Multiple Sclerosis Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis
Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERβ-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERβ in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERβ to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.
Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
The Molecular Basis for Remyelination Failure in Multiple Sclerosis.
Myelin sheaths in the central nervous system (CNS) insulate axons and thereby allow saltatory nerve conduction, which is a prerequisite for complex brain function. Multiple sclerosis (MS), the most common inflammatory autoimmune disease of the CNS, leads to the destruction of myelin sheaths and the myelin-producing oligodendrocytes, thus leaving behind demyelinated axons prone to injury and degeneration. Clinically, this process manifests itself in significant neurological symptoms and disability. Resident oligodendroglial precursor cells (OPCs) and neural stem cells (NSCs) are present in the adult brain, and can differentiate into mature oligodendrocytes which then remyelinate the demyelinated axons. However, for multiple reasons, in MS the regenerative capacity of these cell populations diminishes significantly over time, ultimately leading to neurodegeneration, which currently remains untreatable. In addition, microglial cells, the resident innate immune cells of the CNS, can contribute further to inflammatory and degenerative axonal damage. Here, we review the molecular factors contributing to remyelination failure in MS by inhibiting OPC and NSC differentiation or modulating microglial behavior.
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