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).