While nucleic acid therapeutics have shown promise in rodent and nonhuman primate models of CNS diseases, all double blind clinical trials to date have failed. One likely explanation for this failure is poor therapeutic distribution in targeted brain regions. For example, post-mortem studies of patients with Parkinson's Disease receiving intraparenchymal injections of AAV-NTN demonstrated very limited protein expression. In this study, only 10-16% of the transgene was observable post-mortem using a standard injection approach with a maximum of 15% of TH up- regulation. Although the results of this study were disappointing, there is strong evidence that this gene therapy approach is valid and is capable of being highly effective. A primary difference between non-human primate studies and human trials has been that the monkeys receive a wide distribution of infection, while infection in humans is dramatically reduced due to the much larger brain volumes. Based on the results of the studies conducted by Ceregene (AAV-NTN), Sanofi-Genzyme (AAV-hAADC), and Neurologix (AAV-GAD), we conclude that the failure of these clinical trials was due in part to inadequate therapeutic delivery. Today, distribution of therapeutic to a brain region such as the striatum requires multiple trajectories per hemisphere using a large gauge cannula. Performing serial infusions using a straight cannula along multiple trajectories extends surgical time and increases the risk of hemorrhage and tissue trauma. A new system is needed to improve the efficiency and effectiveness of nucleic acid therapeutic delivery in the brain. We propose development of an MR-compatible stereotactic delivery device capable of achieving widespread nucleic acid therapeutic coverage of common CNS disease targets. The device will be tested in rats using a viral vector substitute. The proposed delivery technology is nonspecific and could be applied to the treatment of a wide range of CNS conditions where nucleic acid therapeutics are being investigated, including Huntington?s Disease (IONIS-HTT), Parkinson's Disease (VY-AADC), and Sanfilippo syndrome (LYS-SAF302).
Nucleic acid therapeutics for CNS diseases have shown promising signs of efficacy in animal models, only to disappoint in human clinical trials. The primary difference between successful non-human primate studies and human trials was that the animal received broad therapeutic coverage of target brain regions while coverage of target regions in humans was dramatically reduced. We therefore believe that inadequate delivery tools and methods were a contributing factor to the failure of these trials, and propose the development of a stereotactic system to efficiently deliver nucleic acid therapeutics with improved distribution.
