RESUMO
The 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.
Assuntos
Expressão Gênica , Degeneração Neural/genética , Degeneração Neural/terapia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Interferência de RNA/fisiologia , RNA Mensageiro/metabolismo , Ataxias Espinocerebelares/patologia , Adenoviridae , Animais , Ataxina-1 , Ataxinas , Northern Blotting , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Glutamina , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/farmacologia , Proteínas Nucleares/farmacologia , Plasmídeos/genética , Desempenho Psicomotor/efeitos dos fármacos , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução GenéticaRESUMO
Huntington's disease (HD) is a fatal, dominant neurogenetic disorder. HD results from polyglutamine repeat expansion (CAG codon, Q) in exon 1 of HD, conferring a toxic gain of function on the protein huntingtin (htt). Currently, no preventative treatment exists for HD. RNA interference (RNAi) has emerged as a potential therapeutic tool for treating dominant diseases by directly reducing disease gene expression. Here, we show that RNAi directed against mutant human htt reduced htt mRNA and protein expression in cell culture and in HD mouse brain. Importantly, htt gene silencing improved behavioral and neuropathological abnormalities associated with HD. Our data provide support for the further development of RNAi for HD therapy.