Optimizing Direct Delivery of Nucleic Acid Therapeutics

Project Summary While nucleic acid therapeutics have shown promise in rodent and nonhuman primate models of CNS diseasesall double blind clinical trials to date have failedOne likely explanation for this failure is poor therapeutic distribution in targeted brain regionsFor examplepost mortem studies of patients with Parkinsonandapos s Disease receiving intraparenchymal injections of AAV NTN demonstrated very limited protein expressionIn this studyonlyof the transgene was observable post mortem using a standard injection approach with a maximum ofof TH upregulationAlthough the results of this study were disappointingthere is strong evidence that this gene therapy approach is valid and is capable of being highly effectiveA primary difference between non human primate studies and human trials has been that the monkeys receive a wide distribution of infectionwhile infection in humans is dramatically reduced due to the much larger brain volumesBased on the results of the studies conducted by CeregeneAAV NTNSanofi GenzymeAAV hAADCand NeurologixAAV GADwe conclude that the failure of these clinical trials was due in part to inadequate therapeutic deliveryTodaydistribution of therapeutic to a brain region such as the striatum requires multiple trajectories per hemisphere using a large gauge cannulaPerforming serial infusions using a straight cannula along multiple trajectories extends surgical time and increases the risk of hemorrhage and tissue traumaA new system is needed to improve the efficiency and effectiveness of nucleic acid therapeutic delivery in the brainWe propose development of an MR compatible stereotactic delivery device capable of achieving widespread nucleic acid therapeutic coverage of common CNS disease targetsThe device will be tested in rats using a viral vector substituteThe 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 investigatedincluding Huntington s DiseaseIONIS HTTParkinsonandapos s DiseaseVY AADCand Sanfilippo syndromeLYS SAFProject Narrative Nucleic acid therapeutics for CNS diseases have shown promising signs of efficacy in animal modelsonly to disappoint in human clinical trialsThe 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 reducedWe therefore believe that inadequate delivery tools and methods were a contributing factor to the failure of these trialsand propose the development of a stereotactic system to efficiently deliver nucleic acid therapeutics with improved distribution