Huntington's disease (HD) is a severely debilitating heritable neurodegenerative condition for which there currently is no treatment. Because there is a genetic test available for HD, intervention prior to disease onset would be possible if an effective treatment were available. The growth factor neurturin (NTN) has been shown to effectively ameliorate neural degeneration in rodent models of HD when delivered to the brain. However, as a protein growth factor, NTN will not readily access brain targets following systemic administration. Gene transfer using a viral vector is a promising method for delivering growth factors to specific regions of the brain, and the adeno-associated virus (AAV) based vector is in many ways the best-suited vector for this application. As a first step towards developing AAV-delivered NTN (AAV-NTN) for the treatment of HD, we will test the efficacy of AAV-NTN in two distinct rodent models of HD: the 3-nitroproprionic acid (3NP) lesion in Lewis rats, and N171-82Q transgenic mice. The ability of AAV-NTN to prevent neurodegeneration and motor deficits in 3NP lesioned rats, and reduce accumulation of neuronal intranuclear inclusions, and motor and cognitive deficits in N171-82Q transgenic mice will be assessed. Successful results from these studies will lead to safety studies in rats, safety and efficacy studies in non-human primates, and if indicated, the filing of an IND and clinical trials in HD patients.
