Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease.

Autor:	Oliveira Miranda C; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Marcelo A; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Silva TP; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Barata J; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Vasconcelos-Ferreira A; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Doctoral Programme of Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal., Pereira D; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Doctoral Programme in Experimental Biology and Biomedicine, CNC - University of Coimbra, Rua Larga, Faculdade de Medicina, Pólo I, 1° andar, 3004-504 Coimbra, Portugal., Nóbrega C; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Duarte S; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Barros I; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Alves J; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Sereno J; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, Edifício do ICNAS, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Institute of Nuclear Science Applied to Health, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Petrella LI; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, Edifício do ICNAS, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Institute of Nuclear Science Applied to Health, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Castelhano J; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, Edifício do ICNAS, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Institute of Nuclear Science Applied to Health, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Paiva VH; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; MARE - Marine and Environmental Sciences Centre, Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal., Rodrigues-Santos P; Immunology Institute, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, 3004-504, Portugal; Center of Investigation in Environment, Genetics and Oncobiology, Apartado 9015, 3001-301, Coimbra, Portugal., Alves V; Immunology Institute, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal; Immunology and Oncology Laboratory, Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, 3004-504, Portugal; Center of Investigation in Environment, Genetics and Oncobiology, Apartado 9015, 3001-301, Coimbra, Portugal., Nunes-Correia I; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Nobre RJ; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão - Pólo II, Rua Dom Francisco de Lemos, 3030-789 Coimbra, Portugal; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Gomes C; Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Castelo-Branco M; Centre for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Coimbra Institute for Biomedical Imaging and Translational Research, Edifício do ICNAS, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; Institute of Nuclear Science Applied to Health, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal., Pereira de Almeida L; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculdade de Medicina, Rua Larga, Pólo I, 1° andar, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address: luispa@cnc.uc.pt.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2018 Sep 05; Vol. 26 (9), pp. 2131-2151. Date of Electronic Publication: 2018 Jul 12.
DOI:	10.1016/j.ymthe.2018.07.007
Abstrakt:	Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders. (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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