Image-Guided Convective Delivery of AAV Vectors
Improving Delivery of Parkinson's Disease Therapeutics to th, 2008
Gene transfer technology holds promise to permanently alter the natural course of PD. However, in order for this technology to work there is a critical need for safe, reproducible brain administration of viral vectors. We are exploring co-infusion into the brain of a viral vector (AAV2) along with an MRI contrast reagent to track the movement of AAV2 in real time. We want to show that the pattern of distribution of the contrast reagent matches the distribution of the gene therapy product, in this case the growth factor, GDNF. If so, then we can monitor infusions of AAV2 with intra-operative MRI.
Non-human primates will receive striatal infusions of AAV2-GDNF along with MRI contrast reagent. We will compare the volume of distribution of the contrast reagent calculated by MRI with the volume of AAV2 vector and then GDNF distribution calculated from immunohistochemical analysis of the pattern of GDNF expression. We expect that there will be a fixed relationship between these parameters. We will also be testing a new MRI-compatible infusion cannula to determine whether it is safe to use in the primate brain. Tests will be conducted to assess whether the cannula causes any overt tissue damage.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Gene therapy holds great promise for the treatment of PD, particularly with respect to the use of the growth factor, GDNF, because it has previously been shown to ameliorate PD symptoms. By delivering an engineered virus that carries the GDNF gene into the striatum, local neurons can be instructed to make GDNF. But this technology depends critically on accurate and predictable targeting of the virus to the correct regions of the brain.
We expect that the data we collect will be used to compile an Investigational New Drug Application for MRI-monitored AAV2-GDNF infusion into the striatum for the treatment of PD.
INTERIM PROGRESS REPORT
During the first year of funding we were able to accurately predict the movement of viral particles injected into the brain of animals using gadolinium tracer. We tracked the movement of viral particles and also distribution of transduction and expression of the AADC and GDNF virus and corresponding protein. In year two, we will be optimizing the methodology by utilizing the clinically appropriate frameless guiding system in order to translate these experiments into a clinical setting.
Kinetics Foundation Chair in Translational Research, and Professor in Residence of Neurosurgery and Neurology, and Director of the Translational NeuroTherapy Center at University of California, San Francisco