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A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept Studies

3: Vagus Nerve Delivery of AAV9 to Treat Autonomic Nervous System Dysfunction in Giant Axonal Neuropathy

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Gene Therapy in Large Animal Models
Location: Room 204
Start Time: 5/16/2022 10:45
End Time: 5/16/2022 11:00

Giant axonal neuropathy (GAN) is a rare pediatric disorder caused by autosomal recessive loss-of-function mutations in the GAN gene. A Phase I study (NCT02362438) is underway to test the safety of lumbar-injected, intrathecal (IT) delivered scAAV9/JeT-GAN to treat the most severe aspects of GAN. While GAN is primarily described as a progressive motor and sensory neuropathy, pathology is apparent throughout the autonomic nervous system (ANS) and patients frequently present with enteric and autonomic dysfunction. The distribution of IT-delivered AAV9 to peripheral ganglia is limited, so we hypothesized that if AAV9/GAN is also delivered via the vagus nerve (VN) then critical ANS neurons will be transduced, resulting in a greater amelioration of ANS dysfunction as compared to IT delivery alone. We tested this approach in a GAN rat model that we previously developed. Adult GAN rats received a single IT or a combination IT and vagus nerve injection of AAV9/GAN or vehicle and were monitored for up to 20 months post-injection. Rats were implanted with telemetry devices to record blood pressure, heart rate, respiration and body temperature under basal conditions and following ANS stimulation. At baseline, there was not a detectable difference in autonomic function between WT and GAN KI rats. However, upon challenge of the autonomic nervous system with pilocarpine, GAN KI rats had abnormal blood pressure, heart rates and respiration as compared to WT rats. The effect of pilocarpine on body temperature was normal in the KI rats. IT only delivery of AAV9/GAN improved respiration and blood pressure in GAN KI rats. Combined IT+VN delivery of AAV9/GAN showed greater efficacy than IT alone with normalization of respiration, blood pressure and heart rate responses as compared to control WT rats. Histological analysis of tissues also showed an unexpected additive benefit of combined IT+VN delivery in preventing nerve fiber loss within the dorsal columns of the spinal cord as compared to IT alone treatment. These results support that a simultaneous dual-route administration could be proposed for future patients. To our knowledge, VN injection of AAV has not been utilized in large animals or humans, so we tested the feasibility of this approach in dogs. Adult hounds received a direct vagus nerve injection of AAV9/CBh-GFP and were observed for 3 weeks post-injection. Vocalization, weight, eating and fecal output were monitored pre and post-surgery. Overall, the injections were well-tolerated. Post-mortem analysis showed that in agreement with our previous studies in rats, there was efficient targeting of vagal neurons of the nodose ganglia, dorsal motor nucleus, visceromotor neurons and fibers of the nucleus ambiguous, and viscerosensory neurons and fibers of the nucleus tractus solitarius. Together these results support that direct VN delivery of AAV9 can efficiently transduce neurons critical for ANS function in large animals. Previously, we found that rats pre-immunized with AAV9 had efficient GFP transduction in vagal nerve fibers and neurons when they received a second dose of AAV9 via the vagus nerve, albeit to a reduced level as compared to naïve rats. Histological analysis showed an excellent safety profile without evidence of neuroinflammation or significant chronic inflammatory infiltrates. It remains to be determined in a large animal if direct vagal nerve injection could allow for redosing of AAV9 to target the ANS in subjects that previously received an AAV9 gene therapy. Additional studies are warranted to translate this approach into clinical testing for patients with GAN. Results from these studies are immediately applicable to GAN but may extend to treating a wider variety of neurological diseases.

Rachel M. Bailey1, Diane Armao2, Irvin Garza1, Yuhui Hu1, Sydni Holmes1, Alejandra Rozenberg2, Angela Price1, Steven J. Gray1

1UT Southwestern Medical Center, Dallas, TX,2University of North Carolina at Chapel Hill, Chapel Hill, NC
  R.M. Bailey: 1; Commercial Interest i.e. Company X; Taysha Gene Therapies. 1; What was received? i.e. Honorarium; Royalty.

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