AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease

被引:123
作者
Franich, Nicholas R. [1 ]
Fitzsimons, Helen L. [2 ]
Fong, Dahna M. [1 ]
Klugmann, Matthias [3 ]
During, Matthew J. [1 ,4 ]
Young, Deborah [1 ,5 ]
机构
[1] Univ Auckland, Dept Mol Med & Pathol, Auckland 1, New Zealand
[2] Neurologix, Ft Lee, NJ USA
[3] Johannes Gutenberg Univ Mainz, Dept Physiol Chem, D-6500 Mainz, Germany
[4] Ohio State Univ, Coll Med, Dept Mol Virol Immunol & Med Genet, Columbus, OH USA
[5] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand
关键词
D O I
10.1038/mt.2008.50
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
We report the characterization of a new rapid-onset model of Huntington's disease (HD) generated by adeno-associated virus (AAV) vector-mediated gene transfer of N-terminal huntingtin (htt) constructs into the rat striatum. Expression of exon 1 of mutant htt containing 70 CAG repeats rapidly led to neuropathological features associated with HD. In addition, we report novel data relating to neuronal transduction of AAV vectors that modulated the phenotype observed in this model. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that AAV vector-mediated expression in the striatum increased by > 100-fold as compared to the endogenous htt level. Moreover, AAV vectors exhibited nonuniform transduction patterns in striatal neuronal populations, as well as axonal transport leading to transduction and neuronal cell death in the globus pallidus and substantia nigra (SN). These findings may inform future studies that utilize AAV vectors for neurodegenerative disease modeling. Further, RNA interference (RNAi) of mutant htt expression mediated by virus vector delivery of short hairpin RNAs (shRNAs) ameliorates early-stage disease phenotypes in transgenic mouse models of HD. However, it has not been reported whether shRNA-mediated knockdown of mutant htt expression is neuroprotective. AAV-shRNA was shown to mediate a dramatic knockdown of HD70 expression, preventing striatal neurodegeneration and concomitant motor behavioral impairment. These results provide further support for the use of AAV vector-mediated RNAi as a therapeutic strategy for HD.
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页码:947 / 956
页数:10
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