AAV Vector–mediated RNAi of Mutant Huntingtin Expression Is Neuroprotective in a Novel Genetic Rat Model of Huntington's Disease

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 le...

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Bibliographic Details
Published in:Molecular therapy 2008-05, Vol.16 (5), p.947-956
Main Authors: Franich, Nicholas R, Fitzsimons, Helen L, Fong, Dahna M, Klugmann, Matthias, During, Matthew J, Young, Deborah
Format: Article
Language:English
Subjects:
Animals
Atrophy
Brain
Cell death
Corpus Striatum - metabolism
Dependovirus - genetics
Exons
Gene therapy
Genetic Therapy - methods
Genetic Vectors
Genotype & phenotype
Humans
Huntingtin Protein
Huntington Disease - genetics
Huntington Disease - therapy
Huntingtons disease
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurodegeneration
Neurons - metabolism
Neuropathology
Neuroprotective Agents - pharmacology
Nuclear Proteins - biosynthesis
Nuclear Proteins - genetics
Phenotype
Rats
Reverse Transcriptase Polymerase Chain Reaction
RNA Interference
Toxicity
Vectors (Biology)
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Summary: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.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2008.50