Introduction Drug delivery to the brain remains challenging mainly due to the blood brain barrier. We previously reported on cisterna magna (CM) microcatheterization through a lumbar puncture for gene therapy of Tay Sachs disease. Technology for CFS drainage in treatment of hydrocephalus (eShunt,Ceravasc) has enabled transvenous access to the cerebellopontine angle (CPA) cistern
Aim of Study We hypothesize that CPA injection is safe and comparable to the biodistribution of scAAV9-CB-GFP observed with CM injection.
Methods Eight sheep were injected with scAAV9-CB-GFP into the CPA (n=4) and CM (n=4). Through a lumbar puncture, a 1.7F microcatheter with 0.014’ micro-guidewire was navigated into either the CPA cistern or CM under fluoroscopy. Cone-beam computed tomography fused with MRI was used to confirm accurate microcatheter placement. scAAV9-CB-GFP(1.0 x 1014 vg in 3 ml) was injected at 200µl/min. Animals were sacrificed 3 weeks post-procedure. Anti-GFP antibody immunohistochemistry was performed and vector genome biodistribution was determined by qPCR.
Results GFP immunohistochemistry and qPCR showed stronger transduction profiles in the parietal cortex in the CPA cohort compared to CM and modest increase of GFP in the dorsal midbrain. Strong immunoreactivity was also observed in the ventral aspect of the cingulate gyrus. Vector genome quantification of different brain structures showed comparable results between CPA and CM injection routes.
Conclusion CPA delivery of AAV9 resulted in increased transduction of the parietal and cingulate cortex, comparable to that observed with CM injections. Provided is preliminary evidence that CPA infusion of gene therapy is safe and provides widespread distribution throughout the brain.
Disclosure of Interest AM, CH,BB: Cerevasc
HB, VA, EH, aL, RK, HG: Nothing to disclose
MG: No relevant disclosures
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