Developing Brain Penetrable AAV Gene Therapy for Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD)

Project Summary - Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive neurologic disorder due to failed catabolism of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Patients with SSADHD exhibit intellectual disability with autistic features and epilepsy (with a high rate of sudden unexpected death in epilepsy, SUDEP). SSADHD symptoms are largely a result of the namesake enzyme deficit that leads to the pathologic accumulation of GABA and its metabolic by-product γ-hydroxybutyrate (GHB). The present standard of care for SSADHD includes behavioral therapy and anti-seizure drug medications – but these treatment options are ineffective and do not address the underlying genetic root cause. Notably, recent targeted drug trials have failed to improve core SSADHD symptoms, highlighting a major unmet medical need for disease- modifying treatment such as gene replacement therapy. Our proof-of-concept studies demonstrated phenotype reversal in SSADHD mice from a symptomatic stage when treated with a blood-brain barrier (BBB) penetrable adeno-associated virus capsid (AAV-PHP.eB) containing a novel viral payload encompassing a human full length native promoter (FLnP) coupled with a functional copy of the human SSADH-encoding gene ALDH5A1 (AAV-FLnP-hALDH5A1, US patent filed). Importantly, post-mortem analyses of treated mice revealed a direct relationship between survival and transgene expressions in the cerebral cortex and myocardium, highlighting a need for dose finding upon clinically relevant AAV delivery. Galibra Neuroscience, Inc. has obtained a license to develop AAV-FLnP-hALDH5A1, now named GAL005, to further determine the optimal dose in an AAV-BI-hTFR1 capsid, an engineered serotype that utilizes human transferrin receptors on the BBB to penetrate into the CNS. We will use a “humanized” mouse strain in which exons 4 – 19 of the mouse Tfrc gene encoding the extracellular domain are replaced by a knock-in of the corresponding region of human TFRC gene (i.e., TFRC KI mice) to measure biodistribution of GAL005 upon intravenous delivery (via retro-orbital injection) for clinical translation relevance. In this R41 STTR-Phase I proposal, we focus on two Specific Aims to advance the clinical readiness of GAL005 for the investigational new drug (IND)-enabling studies. This project will subcontract to the Rotenberg lab at BCH for biodistribution of GAL005 transfection in humanized mice (Aim 1). In parallel, an SSADHD model mouse developed by the Rotenberg lab will be crossed with TFRC KI mice, providing a preclinical model for final efficacy testing (Aim 2). In summary, we will measure payload biodistribution and preclinical toxicology of GAL005 and create a new humanized SSADHD mouse strain compatible with GAL005. If successful, this work will form the basis for completing IND-enabling studies and proceeding to the clinic, bringing the first CNS- and peripheral-targeting gene replacement therapy for a devastating ultra-rare orphan disease to market.