DESCRIPTION (provided by principal investigator): Huntington's disease (HD) is a autosomal dominant neurodegenerative disorder which is normally fatal and untreatable and results in a severe movement disorder, cognitive and neuropsychiatric abnormalities. HD is caused by a pathological expansion of polyglutamine repeats in the Huntingtin gene (mhtt), resulting in the eventual loss predominantly of striatal medium spiny neurons although dysfunction and/or degeneration of other brain regions can occur as well. While the mechanism of mhtt-induced neurodegeneration remains unknown, apoptosis (programmed cell death) has emerged as a potential mediator in a variety of prior studies. X-linked inhibitor of apoptosis (XIAP) is the most potent member of a family of apoptosis inhibitor proteins, which is known to bind to and block the function of effectors of apoptosis including caspases and mitochondrial cell death proteins Smac and Omi. We have long used the adeno-associated virus (AAV) vector as a gene transfer agent for neurodegenerative diseases and have recently reported the use of AAV in the first human trial of gene therapy for Parkinson's disease. Based upon this, we received a pilot application R21 NS055003 to examine the potential of AAV-XIAP gene therapy in the striatum as a novel therapy for HD. We have now demonstrated that intrastriatal AAV-XIAP can reverse motor dysfunction in both the N171-82Q and YAC128 transgenic mouse models of HD. The normally shortened lifespan of N171 mice were also significantly extended by 20% while statistically complete prevention of neurodegeneration was demonstrated in the normal lifespan YAC128 mice. While this pilot data along with cell culture studies strongly supports the potential of AAV-XIAP as a potential gene therapy agent, here we propose to address several important remaining questions which have significance for both understanding the pathogenesis of HD as well as specifically translating AAV-XIAP into a clinical gene therapy agent. Aim 1 will further address the breadth and mechanism of AAV-XIAP-mediated neuro protection. Since death was used as an endpoint for the pilot N171 study, histological analysis was not performed so we will determine the effect of AAV-XIAP on neuropathology in this line just prior to death. We will also use XIAP point mutants lacking certain specific functions to explore potential mechanisms of XIAP-mediated neuro protection in order to better define pathways which may be targeted for novel neuro protective therapeutics in HD. In both N171 and YAC128 models, motor function was improved to wild-type levels prior to the reported age at which neuro degeneration normally ensues. This suggests an improvement in neuronal dysfunction by XIAP distinct from neuro protective effects. Aim 2 will use both striatal slices and a novel transgenic HD mouse to determine the effect of XIAP on dopamine receptor signaling in HD striatal neurons. Finally, aim 3 will address certain remaining questions which would inform a potential human clinical trial of AAV-XIAP for HD. This study should help develop AAV-XIAP into a human therapeutic and provide novel information to develop drugs to reverse neuronal dysfunction and/or loss in HD. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a lethal and untreatable inherited neurological disorder caused by a mutation in the Huntington (htt) gene. Here we propose to use gene therapy to introduce a powerful cell protective gene called XIAP into brain of mouse HD models. The results of this application should lead to a better understanding of the currently unknown mechanism of cell death and dysfunction in the brains of HD could lead to novel therapies to reverse this process. Given our promising preliminary data and recent use of gene therapy in human Parkinson's disease, this application may also facilitate development of XIAP gene therapy for human HD.