Huntington's disease (HD) is a progressive devastating neurodegenerative disorder that results in motor dysfunction, cognitive impairment and development of psychiatric symptoms. HD is characterized by a loss of srtiatal neurons. It is caused by a mutant form of a protein termed huntingtin (htt). The mutation is an expansion of CAG repeats in exon 1 of the HD gene. This expansion, which is translated into a polyglutamine tract, causes mutant htt to acquire a gain of toxic function. Various hypotheses have been brought forward as to what this toxic function may be. One hypothesis points to a disruption, caused by mutant htt, in the expression of other genes required for neuronal survival. It has been shown that htt is required during embryogenesis but the function of both mutant and normal htt in adults remains unknown. By using a well established HD-like mouse model (R6/2) this proposal will study the effects of reducing expression of mutant htt in striatal neurons. This reduction will be achieved by delivering RNA cleaving enzymes (ribozymes) that specifically recognize and cleave the htt mRNA. These ribozymes will be delivered by stereotaxic injections using a recombinant adeno-associated viral vector (rAAV) into the striatum of R6/2 mice. Reducing striatal mutant htt expression will help us elucidate the function of this protein in adult mouse striatum and identify which genes, if any, are directly inhibited by mutant htt. This proposal will also address the therapeutic potential of delivering trophic factors into the brain of R6/2 mice. Results gained from this study will enhance our understanding of the molecular pathogenesis of HD and offer new therapeutic alternatives to a fatal disease with no known cure.
| Denovan-Wright, Eileen M; Rodriguez-Lebron, Edgardo; Lewin, Alfred S et al. (2008) Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo. Neurobiol Dis 29:446-55 |
| Rodriguez-Lebron, Edgardo; Denovan-Wright, Eileen M; Nash, Kevin et al. (2005) Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Mol Ther 12:618-33 |
