Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease
| Autor: | Joana Alves, José Sereno, Luís Pereira de Almeida, Lorena I. Petrella, Miguel Castelo-Branco, Isabel Nunes-Correia, Sónia Duarte, Catarina Oliveira Miranda, Adriana Marcelo, Dina Pereira, Paulo Rodrigues-Santos, Teresa Silva, Vitor H. Paiva, Clévio Nóbrega, Rui Jorge Nobre, Célia Gomes, João Castelhano, João Barata, Inês Barros, Vera Alves, Ana Vasconcelos-Ferreira |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Oncology congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Glutamic Acid Mice Transgenic Disease Neuropathology Mesenchymal Stem Cell Transplantation Neuroprotection Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Drug Discovery Genetics medicine Animals Ataxin-3 Molecular Biology gamma-Aminobutyric Acid Pharmacology business.industry Mesenchymal stem cell Mesenchymal Stem Cells Machado-Joseph Disease Polyglutamine tract medicine.disease 3. Good health Mice Inbred C57BL Transplantation 030104 developmental biology Spinocerebellar ataxia Molecular Medicine Original Article business Machado–Joseph disease 030217 neurology & neurosurgery |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2018.07.007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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