Abstract Details

Title Intrathecal AAV9-SOD1-shRNA Administration for Amyotrophic Lateral Sclerosis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S5 - Therapeutics in ALS and SMA (1:22 PM-1:33 PM)

Poster/Presentation
Number 003

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.

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

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.

Authors/Disclosures
Gretchen Thomsen PRESENTER	No disclosure on file
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Petra Kaufmann, MD, FAAN (Affinia Therapeutics)	Dr. Kaufmann has received personal compensation for serving as an employee of Affinia Therapeutics. Dr. Kaufmann has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Kaufmann has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for DTx. Dr. Kaufmann has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Taysha Gene Therapies. Dr. Kaufmann has stock in Vigil Neuroscience. The institution of an immediate family member of Dr. Kaufmann has received research support from Cystic Fibrosis Foundation . Dr. Kaufmann has a non-compensated relationship as a Member of a Scientific Advisory Board with NIH that is relevant to AAN interests or activities.
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