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Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease
- Source :
- Molecular Therapy
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....edd1f211b8074eeced694e26871de7ba