This application addresses broad Challenge Area (15): 15-NS-102: Translation of Gene Silencing Therapeutics. The proposed challenge set forth in the RFA is to extend the current understanding of the feasibility and safety of RNA interference (RNAi) therapeutics for the treatment of chronic neurological disorders from rodent models of disease to a more clinically relevant species. The current proposal outlines a systematic approach to translate work we, and others, have undertaken to investigate RNAi as a potential therapy for the neurological disorder, Huntington's disease (HD) in cell culture and rodent models and apply these findings to the non-human primate (NHP). HD is a fatal, genetic disorder caused by mutations in HTT, which encodes huntingtin (HTT), and affects approximately 30,000 people in the United States alone. HD is characterized by hyperkinetic movements, loss of cognitive abilities and severe emotional disturbances. RNAi has emerged as a candidate therapy for HD because it can reduce disease gene expression. However two critical questions important to the general application of RNAi to brain disorders, and of specific importance to HD, have yet to be addressed. One, is long-term application of therapeutic RNAi to primate brain feasible for chronic neurodegenerative diseases like HD? Second, is the primate brain tolerant of knock down of both normal and mutant HTT alleles? To address the former question we, and others, have built the tools necessary for sustained expression of candidate therapeutic RNAi in brain using viral vectors. In this manner, questions of chronic application can be tested without re-delivery issues. In this proposal we will test the feasibility of long-term therapeutic RNAi using recombinant adeno-associated virus (AAV) vectors. To address the second question, we have built and tested therapeutic RNAi in rodent models of HD, and show improvements in disease-specific phenotypes, including survival. With these tools we can now answer the questions posed in a more relevant model, the normal NHP (rhesus macaque;Macaca mullata). The proposed studies are a collaboration between two laboratories: the Davidson Laboratory at the University of Iowa and the Ojeda Laboratory at the Oregon National Primate Research Center (ONPRC). The Davidson Laboratory has experience developing and testing RNAi therapeutics in rodents, while the Ojeda Laboratory has expertise in stereotaxic delivery of viral vectors to the NHP brain. Also, the ONPRC has methodologies, equipment and personnel in place that, along with Dr. Ojeda's group, can evaluate if application of HTT suppression, or RNAi in general, induces neuropathology or neurological symptoms after delivery of RNAi expression vectors to NHP brain. While these proof-of-principle studies will provide a platform to rigorously evaluate RNAi therapeutics for HD, information derived from our work can be applied to RNAi therapies for other chronic, neurological disorders including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (Lou Gherig's disease), dystonia, spinocerebellar ataxias and Rett's Syndrome. Moreover, the results from our studies will provide the necessary tools for laboratories investigating RNAi therapy for other brain disorders in the NHP, such as neuropathic pain, encephalitis, various carcinomas, anxiety and depression. In this work we will test the safety and efficiency of gene therapies designed to treat the fatal neurogenetic disorder, Huntington's disease, in a clinical relevant model, the nonhuman primate. Experiments are designed to test questions relevant to moving therapeutic gene silencing strategies from efficacy studies in rodent models to the clinic, and to address important issues regarding this therapy for Huntington's disease. This work is a collaborative effort between laboratories at the University of Iowa and the Oregon National Primate Research Center at the Oregon Health Sciences University.
In this work we will test the safety and efficiency of gene therapies designed to treat the fatal neurogenetic disorder, Huntington's disease, in a clinical relevant model, the nonhuman primate. Experiments are designed to test questions relevant to moving therapeutic gene silencing strategies from efficacy studies in rodent models to the clinic, and to address important issues regarding this therapy for Huntington's disease. This work is a collaborative effort between laboratories at the University of Iowa and the Oregon National Primate Research Center at the Oregon Health Sciences University.
