Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease

Maria Do Carmo Costa, Katiuska Luna-Cancalon, Svetlana Fischer, Naila S. Ashraf, Michelle Ouyang, Rahil M. Dharia, Lucas Martin-Fishman, Yemen Yang, Vikram G. Shakkottai, Beverly L. Davidson, Edgardo Rodríguez-Lebrón, Henry L. Paulson

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1898-1908
Number of pages11
JournalMolecular Therapy
Issue number10
StatePublished - Oct 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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