Nature Medicine
10, 816 - 820 (2004)
Published online: 4 July 2004; | doi:10.1038/nm1076
RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxiaHaibin Xia1, 2, 8, Qinwen Mao1, 2, 8, Steven L Eliason1, 2, Scott Q Harper1, 2, Inês H Martins1, 2, Harry T Orr3, 4, Henry L Paulson5, Linda Yang6, Robert M Kotin6
& Beverly L Davidson1, 2, 5, 71
Program in Gene Therapy, University of Iowa, Iowa City, Iowa, USA. 2
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA. 3
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. 4
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, USA. 5
Department of Neurology, University of Iowa, Iowa City, Iowa, USA. 6
National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA. 7
Department of Physiology & Biophysics, University of Iowa, Iowa City, Iowa, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Beverly L Davidson beverly-davidson@uiowa.eduThe dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.
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