Introduction Recent technology has enabled transvenous access to the cerebello-pontine angle (CPA) cistern (eShunt, Cerevasc) that is being investigated for CSF drainage in the treatment of hydrocephalous. However, drug delivery to the brain remains a significant challenge due to the blood brain barrier and the large size. We have previously reported on microcatheterization of the cisterna magna (CM) through a lumbar puncture for gene therapy of Tay Sachs disease. We hypothesize that CPA injection is safe and comparable to the biodistribution of scAAV9-CB-GFP delivered via a CM injection.

Methods Eight sheep were injected with scAAV9-CB-GFP into the CPA (n=4) and CM (n=4). Lumbar puncture was performed and a 1.7F braided microcatheter with 0.014’ micro-guidewire was introduced into the subarachnoid space and navigated into either the CPA cistern or CM under fluoroscopic guidance. Cone-beam computed tomography fused with MR imaging was used to confirm accurate final placement of the catheter (Fig). scAAV9-CB-GFP (1.0 x 10¹⁴ vg in 3mL) was injected at 200µl/min. Animals were sacrificed 3 weeks post-procedure. Anti-GFP antibody immunohistochemistry was performed with (Abcam ab290). Vector genome biodistribution determined by qPCR using primers and probes for the BGH poly (A).

Results Immunohistochemistry targeting GFP and qPCR show a stronger transduction profile in the parietal cortex in the CPA cohort compared to CM. In the dorsal midbrain, a modest increase of GFP immunoreactivity was observed in the CPA delivery strategy. Strong immunoreactivity was also observed in the ventral aspect of the cingulate gyrus. Vector genome quantification of different brain structures showed comparable vector genomes between CPA and CM injection routes (Fig). Only modest biodistribution to peripheral liver tissue was observed with both injection routes.

Conclusions CPA delivery of AAV9 resulted in increased transduction of the parietal and cingulate cortex, comparable to that observed with CM injections. These results provide preliminary evidence that CPA infusion of gene therapy, and potentially other therapies such as antisense oligonucleotides or siRNA medications, is safe and provides widespread distribution throughout the brain.

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Abstract E-258 Figure 1

Disclosures A. Malek: 4; C; CereVasc. H. Benatti: None. V. Anagnostakou: None. E. Hall: None. C. Heilman: 4; C; CereVasc. B. Beneduce: 4; C; CereVasc. A. Leporati: None. R. King: None. M. Gounis: 1; C; Research support from the NIH, the United States – Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Balt, Cerenovus, Ceretrieve, CereVasc LLC, Cook Medical, Galaxy Th. 2; C; Consultant on a fee-per-hour basis for Alembic LLC, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, Jacob’s Institute, Medtronic Neurovascular, Mivi Neurosciences, phenox G. 4; C; Imperative Care, InNeuroCo, Galaxy Therapeutics, and Neurogami, and Synchron. H. Gray-Edwards: None.