Journal article
Toward RNAi Therapy for the Polyglutamine Disease Machado–Joseph Disease
Molecular therapy, Vol.21(10), pp.1898-1908
10/01/2013
DOI: 10.1038/mt.2013.144
PMCID: PMC3808129
PMID: 23765441
Abstract
Machado–Joseph disease (MJD) is a dominantly inherited ataxia caused by a polyglutamine-coding expansion in the
ATXN3
gene. Suppressing expression of the toxic gene product represents a promising approach to therapy for MJD and other polyglutamine diseases. We performed an extended therapeutic trial of RNA interference (RNAi) targeting
ATXN3
in a mouse model expressing the full human disease gene and recapitulating key disease features. Adeno-associated virus (AAV) encoding a microRNA (miRNA)-like molecule, miRATXN3, was delivered bilaterally into the cerebellum of 6- to 8-week-old MJD mice, which were then followed up to end-stage disease to assess the safety and efficacy of anti-
ATXN3
RNAi. Despite effective, lifelong suppression of ATXN3 in the cerebellum and the apparent safety of miRATXN3, motor impairment was not ameliorated in treated MJD mice and survival was not prolonged. These results with an otherwise effective RNAi agent suggest that targeting a large extent of the cerebellum alone may not be sufficient for effective human therapy. Artificial miRNAs or other nucleotide-based suppression strategies targeting
ATXN3
more widely in the brain should be considered in future preclinical tests.
Details
- Title: Subtitle
- Toward RNAi Therapy for the Polyglutamine Disease Machado–Joseph Disease
- Creators
- Maria do Carmo Costa - Department of Neurology, University of MichiganKatiuska Luna-Cancalon - University of MichiganSvetlana Fischer - University of MichiganNaila S Ashraf - University of MichiganMichelle Ouyang - University of MichiganRahil M Dharia - University of MichiganLucas Martin-Fishman - University of MichiganYemen Yang - University of MichiganVikram G Shakkottai - University of MichiganBeverly L Davidson - University of IowaEdgardo Rodríguez-Lebrón - University of MichiganHenry L Paulson - University of Michigan
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.21(10), pp.1898-1908
- DOI
- 10.1038/mt.2013.144
- PMID
- 23765441
- PMCID
- PMC3808129
- NLM abbreviation
- Mol Ther
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Publisher
- Nature Publishing Group
- Language
- English
- Date published
- 10/01/2013
- Academic Unit
- Radiology
- Record Identifier
- 9984697734302771
Metrics
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