Pre-Clinical Assessment of Mesenchymal Stem Cell-Based Therapies in Spinocerebellar Ataxia Type 3

Abstract

Motor uncoordination is one of the symptoms of spinocerebellar ataxia type 3/ Machado-Joseph disease (MJD), for which there is no effective treatment. In recent years, stem-cell related therapies begun to be explored for the treatment of neurodegenerative diseases. Beyond their potential for cell replacement therapies, stem cells also act as immunomodulators and neuroprotectors. Despite the evidence of beneficial outcomes in this context, the short duration of the pre and clinical trials and the fact that most patients regressed to the disease stage prior to treatment, highlights the urgency to assess therapeutic efficacy in a chronic fashion. The purpose of this study was to compare the therapeutic efficacy of hMSC transplantation versus administration of their secretome in different disease-relevant regions of the CNS, using a mouse model of MJD. We observed a more marked and sustained therapeutic benefit with hMSC transplantation into the cerebellum when compared to substantia nigra/ striatum or the spinal cord, or to administration of MSC secretome. Funding Statement: This work has been funded the National Ataxia Foundation (NAF), by FEDER, through the Competitiveness Factors Operational Programme (COMPETE), project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, and by National funds through the Foundation for Science and Technology (FCT) under the scope of the project UID/Multi/50026/2019 and fellowships to A.N-C., B. M-P., J. S. C., F. G. T., N. S., R. L., and S. D-S. (SFRH/BPD/118779/2016, SFRH/BD/120124/2016, SFRH/BD/140624/2018, SFRH/BPD/118408/2016, CEECIND/04794/2017, PD/BDE/127836/2016 and PTDC/NEUNMC/3648/2014). Declaration of Interests: The authors have no conflict of interests to report. Ethics Approval Statement: All procedures were conducted in accordance with European regulations (European Union Directive 86/609/EEC). Animal facilities and the people directly involved in animal experiments (A.N.C, B.M.P, J.S.C., S.D.S, S.M., F.G.T, F.L., R.L., N.A.S) as well as the principal investigators (A.J.S. and P.M.) were certified by the Portuguese regulatory entity Direcao Geral de Alimentacao e Veterinaria. All the protocols performed were approved by the Animal Ethics Committee of the Life and Health Sciences Research Institute, University of Minho (Braga, Portugal) and by the national regulatory agency, Direcao Geral de Alimentacao e Veterinaria (DGAV 020317).