1. ¹Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand
2. ²Neurologix, Fort Lee, New Jersey, USA
3. ³Department of Physiological Chemistry, Johannes Gutenberg University, Mainz, Germany
4. ⁴Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA
5. ⁵Department of Pharmacology and Clinical Pharmacology,The University of Auckland, Auckland, New Zealand

Correspondence: Deborah Young, Department of Molecular Medicine and Pathology, The University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: ds.young@auckland.ac.nz

Received 6 December 2007; Accepted 22 February 2008; Published online 25 March 2008.

Abstract

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.