621. Widespread Gene Delivery to the Nonhuman Primate Brain for the Treatment of Huntington's Disease

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG-trinucleotide repeat expansion in a coding exon of a single allele in the HTT locus. In HD, the resulting polyglutamine (polyQ) expansion confers a toxic gain-of-function to the mutant huntingtin protein (mHTT). Reduction of expression of mHTT using gene silencing by RNA interference (RNAi) may confer transformative disease modifying therapeutic approach for HD. Adeno associated vectors (AAV) provide an ideal delivery system for nucleic acid therapeutics and have the potential to allow for long lasting and continuous expression of these huntingtin lowering RNAi in the brain. Despite this promise, global delivery of AAV to the adult brain remains an elusive goal. Furthermore, the appropriate brain areas to target for achieving transformative therapeutic benefit in HD patients remain to be defined. Postmortem analyses of HD patient brains reveal extensive medium spiny neuronal loss in the striatum, in addition to loss of pyramidal neurons in the cerebral cortex and hippocampus. Recent studies in rodent models suggest that simultaneous targeting of striatum and cortex is more efficacious than targeting either individually. Thus, available evidence suggests that delivery of Htt-lowering therapeutics to both striatal and cortical regions may provide optimal therapeutic efficacy. The current study demonstrate for the first time the successful use of an AAV targeting strategy that leads to viral transduction in key brain areas considered to be important for HD pathology. The study compared the efficiency of transduction of AAV1 and AAV2 vectors in the rhesus monkey brain following intra-striatal injection. Both vectors encoded green fluorescent protein (GFP) under control of a hybrid CMV enhancer/chicken beta-actin promoter. One month following injection, brains were analyzed for distribution of GFP-positive cells. We found that the AAV1 vector provided extensive delivery to the majority of the primate striatum, and additionally transduced large numbers of cells within the cerebral cortex, thalamus, and hippocampus. In summary, the data suggest that intrastriatal delivery maybe sufficient for the delivery of nucleic acid-based therapeutics to multiple areas of the human brain relevant in HD.