title: Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease.
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.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Maria do Carmo
authors.initials: Mdo C
authors.lastname: Costa
authors.forename: Katiuska
authors.initials: K
authors.lastname: Luna-Cancalon
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fischer
authors.forename: Naila S
authors.initials: NS
authors.lastname: Ashraf
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.forename: Rahil M
authors.initials: RM
authors.lastname: Dharia
authors.forename: Lucas
authors.initials: L
authors.lastname: Martin-Fishman
authors.forename: Yemen
authors.initials: Y
authors.lastname: Yang
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Shakkottai
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.forename: Edgardo
authors.initials: E
authors.lastname: Rodríguez-Lebrón
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D017827:Machado-Joseph Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3