在脊髓小脑共济失调模型中，RNA干扰抑制多聚谷氨酰胺诱导的神经退行性变。

RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.

作者信息

Xia Haibin, Mao Qinwen, Eliason Steven L, Harper Scott Q, Martins Inês H, Orr Harry T, Paulson Henry L, Yang Linda, Kotin Robert M, Davidson Beverly L

机构信息

Program in Gene Therapy, University of Iowa, Iowa City, Iowa, USA.

出版信息

Nat Med. 2004 Aug;10(8):816-20. doi: 10.1038/nm1076. Epub 2004 Jul 4.

DOI:10.1038/nm1076

PMID:15235598

Abstract

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.

摘要

主要的多聚谷氨酰胺扩增疾病，包括1型脊髓小脑共济失调（SCA1）和亨廷顿病，是进行性、无法治疗的神经退行性疾病。在SCA1和亨廷顿病的诱导性小鼠模型中，突变等位基因表达的抑制改善了疾病表型。因此，设计用于抑制突变基因表达的疗法将是有益的。在此，我们评估RNA干扰（RNAi）在SCA1小鼠模型中抑制由突变型ataxin-1引起的多聚谷氨酰胺诱导的神经退行性变的能力。小脑内注射后，表达短发夹RNA的重组腺相关病毒（AAV）载体显著改善了运动协调性，恢复了小脑形态，并消除了SCA1小鼠浦肯野细胞中特征性的ataxin-1包涵体。我们的数据在体内证明了RNAi作为显性神经退行性疾病疗法的潜在用途。