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Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors

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Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Selective estrogen receptor modulators enhance CNS remyelination independent of estrogen receptors Kelsey A. Rankin1, Feng Mei1, Kicheol Kim1, Yun-An A. Shen1, Sonia R. Mayoral1, Caroline Desponts2, Daniel S. Lorrain2, Ari J. Green1, Sergio E. Baranzini1, Jonah R. Chan1 and Riley Bove1 1University of California, San Francisco, Weill Institute for Neurosciences, Department of Neurology 2Inception Sciences, San Diego, CA https://doi.org/10.1523/JNEUROSCI.1530-18.2019 Received: 11 June 2018 Revised: 17 January 2019 Accepted: 20 January 2019 Published: 29 January 2019 Author contributions: K.R., Y.-A.A.S., A.J.G., J.R.C., and R.B. designed research; K.R., F.M., K.K., Y.- A.A.S., S.R.M., C.D., D.S.L., and S.B. performed research; K.R. analyzed data; K.R. wrote the first draft of the paper; K.R., J.R.C., and R.B. edited the paper; K.R. wrote the paper; F.M. and J.R.C. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. We would like to thank the Innovation Program for Remyelination and Repair at the Weill Institute for Neurosciences at the University of California, San Francisco (UCSF). This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS062796, R01NS097428, R01NS095889, R01NS088155], the National Multiple Sclerosis Society [RG5203A4], The Adelson Medical Research Foundation: ANDP (A130141), the Heidrich Family and Friends and the Rachleff Family Endowments. Correspondence should be addressed to CORRESPONDENCE: Drs. Jonah R. Chan and Riley Bove, University of California San Francisco, Weill Institute for Neuroscience, 675 Nelson Rising Lane, NS260, San Francisco, CA 94143, Tel: (415) 514-9818, Email: [email protected]; [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.1530-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors 1 TITLE 2 Selective estrogen receptor modulators enhance CNS remyelination independent 3 of estrogen receptors 4 5 ABBREVIATED TITLE 6 SERMs enhance remyelination independent of ERs 7 8 AUTHORS 9 Kelsey A. Rankin1, Feng Mei1, Kicheol Kim1, Yun-An A. Shen1, Sonia R. Mayoral1, 10 Caroline Desponts2, Daniel S. Lorrain2, Ari J. Green1, Sergio E. Baranzini1, Jonah R. 11 Chan1, Riley Bove1 12 13 AFFILIATIONS 14 1University of California, San Francisco, Weill Institute for Neurosciences, Department 15 of Neurology 16 2Inception Sciences, San Diego, CA 17 18 CORRESPONDENCE 19 Drs. Jonah R. Chan and Riley Bove 20 University of California San Francisco 21 Weill Institute for Neuroscience 22 675 Nelson Rising Lane, NS260 23 San Francisco, CA 94143 24 Tel: (415) 514-9818 25 Email: [email protected]; [email protected] 26 27 NUMBER OF PAGES 28 25 29 30 NUMBER OF FIGURES 31 6 1 32 33 NUMBER OF WORDS: 34 Abstract: 212 35 Introduction: 165 36 Discussion: 398 37 38 COMPETING FINANCIAL INTERESTS 39 The authors declare no competing financial interests. 40 41 ACKNOWLEDGEMENTS 42 We would like to thank the Innovation Program for Remyelination and Repair at the 43 Weill Institute for Neurosciences at the University of California, San Francisco (UCSF). 44 This work was supported by the National Institutes of Health/National Institute of 45 Neurological Disorders and Stroke [R01NS062796, R01NS097428, R01NS095889, 46 R01NS088155], the National Multiple Sclerosis Society [RG5203A4], The Adelson 47 Medical Research Foundation: ANDP (A130141), the Heidrich Family and Friends and 48 the Rachleff Family Endowments. 49 50 AUTHOR CONTRIBUTIONS 51 Kelsey A. Rankin, Feng Mei, Kicheol Kim, Yun-An A. Shen, Sonia R. Mayoral, Caroline 52 Desponts, Daniel S. Lorrain, and Sergio E. Baranzini performed experiments. Ari Green, 53 Jonah R. Chan, and Riley Bove provided intellectual contributions. Kelsey A. Rankin 54 analyzed the data and wrote the paper. 55 56 ABSTRACT 57 A significant unmet need for patients with multiple sclerosis (MS) is the lack of FDA- 58 approved remyelinating therapies. To this end, we have identified a compelling 59 remyelinating agent, Bazedoxifene (BZA), an EMA-approved (and FDA-approved in 60 combination with conjugated estrogens) selective estrogen receptor modulator (SERM) 61 that could move quickly from bench to bedside. This therapy stands out as a tolerable 62 alternative to previously identified remyelinating agents, or other candidates within this 2 63 family. Using an unbiased high-throughput screen, with subsequent validation in both 64 murine and human oligodendrocyte precursor cells (OPCs), as well as co-culture 65 systems, we find that BZA enhances differentiation of OPCs into functional 66 oligodendrocytes. Using an in vivo murine model of focal demyelination, we find that 67 BZA enhances OPC differentiation and remyelination. Of critical importance, we find 68 that BZA acts independent of its presumed target, the estrogen receptor, in both in vitro 69 and in vivo systems. Employing a massive computational data integration approach, we 70 independently identify 6 possible candidate targets through which SERMs may mediate 71 their effect on remyelination. Of particular interest, we identify EBP (encoding 3β- 72 hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis 73 pathway, which was previously implicated as a target for remyelination. These findings 74 provide valuable insights into the implications for SERMs in remyelination for MS and 75 hormonal research at large. 76 77 SIGNIFICANCE STATEMENT 78 Therapeutics targeted at remyelination failure, which results in axonal degeneration and 79 ultimately disease progression, represents a large unmet need in the multiple sclerosis 80 (MS) population. Here, we have validated a tolerable EMA-approved (FDA-approved in 81 combination with conjugated estrogens) selective estrogen receptor modulator (SERM), 82 Bazedoxifene (BZA), as a potent agent of oligodendrocyte precursor cell (OPC) 83 differentiation and remyelination. SERMs, developed as nuclear estrogen receptor (ER) 84 α and β agonists/antagonists, have previously been implicated in remyelination and 85 neuroprotection, following a heavy focus on estrogens with underwhelming and 86 conflicting results. We show that nuclear ERs are not required for SERMs to mediate 87 their potent effects on OPC differentiation and remyelination in vivo, and highlight EBP, 88 an enzyme in the cholesterol biosynthesis pathway, that could potentially act as a target 89 for SERMs. 90 91 INTRODUCTION 92 In multiple sclerosis (MS), an inflammatory autoimmune disorder of the central nervous 93 system (CNS), an adaptive immune response to unknown CNS antigens results in 3 94 oligodendrocyte damage, loss of myelin, and neurologic dysfunction (Hauser et al., 95 2013). As it has been shown that existing oligodendrocytes are unable to participate in 96 repair (Crawford et al., 2016), newly differentiated oligodendrocytes are required. In the 97 brains of MS patients, oligodendrocyte precursor cell (OPC) proliferation and migration 98 to the lesion site go unhindered, but OPCs are subsequently unable to differentiate into 99 functional oligodendrocytes (Kuhlmann et al., 2008; Frischer et al., 2015). It is generally 100 accepted that disability progression is associated with axon degeneration resulting from 101 remyelination failure (Irvine & Blakemore, 2008; Trapp & Nave, 2008). There are 102 currently no remyelinating therapeutics approved for patients: a clear unmet need in a 103 disease afflicting 850,000 people in the United States and 2.3 million worldwide (Wallin, 104 2017). To target the OPC differentiation block and promote remyelination, we sought to 105 repurpose current FDA-approved compounds. 106 107 MATERIALS AND METHODS 108 Micropillar arrays and quantification of differentiation-promoting compounds 109 Micropillar arrays were fabricated via previously reported methodology (Mei et al., 2014) 110 into 96- or 384-well plates. To test compound effects on OPC proliferation or 111 differentiation, microarrays were coated with poly-L-lysine (Sigma-Aldrich) for 1 hour, 112 then washed 3 times with water. In each well, 40,000 or 150,000 rat OPCs were 113 seeded, respectively. These OPCs were maintained in medium containing DMEM 114 (Invitrogen), B27 (Invitrogen), N2 (Invitrogen), N-acetylcysteine (Sigma-Aldrich), 115 forskolin (Sigma-Aldrich), penicillin-streptomycin (Invitrogen). Medium was 116 supplemented with PDGF-AA (Peprotech) overnight, before removal and treatment with 117 candidate FDA-approved small molecules. For preliminary unbiased screen, 118 compounds were diluted to 1μM and left in medium for 3 days before immunostaining. 119 Each compound was tested in triplicate. For the curated, biased screen of SERMs, 120 candidate compounds were diluted to 500nM and left in medium for 2 days before 121 immunostaining. Each compound was repeated in duplicate. MBP or PDGFRα staining 122 was visualized via 20X microscopy using Zeiss Axio Imager Z1 microscope. 123 124 Purification and culturing of oligodendrocyte precursor cells 4 125 Oligodendrocyte precursor cell (OPC) purification was conducted per the previously 126 validated protocol (Mei et al., 2014).
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