Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease

Mol Ther. 2013 Oct;21(10):1898-908. doi: 10.1038/mt.2013.144. Epub 2013 Jun 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Female
  • Genetic Vectors
  • Humans
  • Machado-Joseph Disease / metabolism
  • Machado-Joseph Disease / pathology
  • Machado-Joseph Disease / physiopathology
  • Machado-Joseph Disease / therapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Motor Activity
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • RNA Interference*
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism*
  • Transduction, Genetic


  • MicroRNAs
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • ATXN3 protein, human
  • Ataxin-3