Cell-based therapeutic strategies for multiple sclerosis

Neil J Scolding,¹ Marcelo Pasquini,² Stephen C Reingold,³ and Jeffrey A Cohen⁴

International Conference on Cell-Based Therapies for Multiple Sclerosis:

¹Department of Neurology, University of Bristol Southmead Hospital, Bristol BS10 5NB, UK

²Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin, Milwaukee, WI 53226, USA

³Scientific and Clinical Research Associates, LLC, Salisbury, CT 06068, USA

⁴Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA

Cell-based therapies, including autologous haematopoietic stem cell transplantation, have generated substantial interest as strategies for immune modulation, neuroprotection, or repair of the damaged CNS in multiple sclerosis. Scolding et al. summarise the status of cell-based therapies and make consensus recommendations for future studies and clinical trials.

Abstract

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.

Keywords: multiple sclerosis and neuroinflammation, stem cells, medical ethics, remyelination, clinical trials

Introduction

With multiple approved disease-modifying therapies (DMTs), there is a broad range of options to treat relapsing-remitting multiple sclerosis (Ingwerson et al., 2016). However, less progress has been made in the treatment of progressive forms of the disease (Shirani et al., 2016). While the positive impact of treatment on reducing the frequency of relapses and accrual of relapse-related disability has been demonstrated, none of the currently available agents halt disease progression or directly promote repair of pre-existing CNS damage. Moreover, all of the approved therapies have potential adverse events that may compromise safety or adherence. All are expected to be ongoing life-long therapies as long as they remain safe and effective. Consequently, there is an imperative for new therapies that (i) are more effective in relapsing-remitting multiple sclerosis, particularly for patients with highly active disease who are at substantial risk for future disability; (ii) are effective in slowing or preventing progression; (iii) have the potential to reverse disability; and (iv) can be used safely with fewer delivery and adherence concerns.

Cell-based therapies have generated substantial interest as potential approaches to address these gaps by working through various mechanisms: regenerating the defective immune system that underlies multiple sclerosis by immunoablation followed by autologous haematopoietic stem cell transplantation (I/AHSCT); modifying both immune reactions and endogenous repair mechanisms using mesenchymal stem cells (MSCs) and other stem cells from bone marrow, adipose tissue, placenta, or other tissues; pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities; or replacing damaged or lost myelin-making oligodendrocytes by transplantation of oligodendrocyte progenitor cells (OPCs) or OPC-like inducible pluripotent stem cells (iPSCs) (Sarkar and Scolding, 2016).

In this review, we discuss the biology and potential utility of these cell-based therapeutic approaches in multiple sclerosis; summarize the progress made to date on testing in multiple sclerosis; discuss practical, scientific, clinical, regulatory, and ethical concerns; and make recommendations for future studies to move this therapeutic area forward. The review is based on an extensive literature search related to cell-based therapies for multiple sclerosis and on discussions at a consensus workshop, the International Conference on Cell-Based Therapies for Multiple Sclerosis, held 19–21 November 2015 in Lisbon Portugal under the auspices of the International Advisory Committee for Clinical Trials in Multiple Sclerosis (see Appendix 1 and Supplementary material for a list of conference participants).

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