Intrathecal AAV9-SOD1-shRNA Administration for Amyotrophic Lateral Sclerosis (S5.003)

Objective: To develop a first-in-human gene therapy for amyotrophic lateral sclerosis (ALS) using intrathecal AAV9-SOD1-shRNA administration.

Background: ALS is a neurodegenerative disease affecting motor neurons, leading to death within 3–5 years of diagnosis. There is no known cure. Twenty percent of genetically-associated ALS cases are linked to mutations in the superoxide dismutase-1 (SOD1) gene. Previously, AAV9-mediated delivery of a small hairpin RNA (shRNA) targeting human SOD1 resulted in efficient downregulation in mice and non-human primates (NHPs). In ALS mice we achieved significant extension in survival with a single administration of an experimental recombinant vector, AAV9-GFP-shRNA-SOD1, in newborn animals and also at later stages after disease onset. These highly promising results set the stage for developing this approach further towards translation to clinical trials.

Design/Methods: We modified the experimental vector for clinical trials using an expression cassette for the delivery of shRNA against human SOD1 devoid of any foreign transgenes (GFP) but maintaining the same cassette size. This was efficiently packaged into an AAV9 viral capsid, creating a new AAV9-SOD1-shRNA (“AVXS-301” herein) translatable to the clinic. Intracerebroventricular delivery (ICV) of AVXS-301 directly into the cerebrospinal fluid (CSF) was performed in the SOD1^G93A ALS mouse model and in NHPs to reduce SOD1 throughout the CNS.

Results: A one-time ICV administration of AVXS-301 lead to significantly improved motor function and prolonged survival in mice overexpressing human mutated SOD1. We tested this strategy in NHP including 3–4 year old cynomolgus macaques and a 10-year old rhesus macaque to facilitate dose extrapolation to human patients. With a single lumbar intrathecal administration we achieved efficient transduction and SOD1 downregulation throughout the entire CNS in these animal models. Importantly, administration of AVXS-301 appeared safe and well tolerated in both mice and NHPs.

Conclusions: Together, these results represent an important advancement towards clinical trials for ALS patients.

Disclosure: Dr. Thomsen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Thomsen holds stock and/or stock options in AveXis, a Novartis company which sponsored research in which Dr. Thomsen was involved as an investigator. Dr. Thomsen has received research support from AveXis, a Novartis company. Dr. Likhite has nothing to disclose. Dr. Corcoran has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Fugere has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, a Novartis company. Dr. Braun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Solano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis. Dr. Kaufmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Meyer has received royalty, license fees, or contractual rights payments from Celenex/Amicus. Dr. Meyer has received research support from Sanofi. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company.