AAV vector-mediated ALDH5A1 gene replacement improves survival and metabolic correction in a severe mouse model of SSADH deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a severe neurometabolic disorder characterized by γ-aminobutyric acid (GABA) and γ-hydroxybutyrate (GHB) accumulation, causing network hyperexcitability, progressive neuroglial pathology, and premature death. Currently, no curative therapy is available. We developed an adeno-associated virus (AAV) vector expressing human aldehyde dehydrogenase 5 family member A1 and assessed its therapeutic efficacy in a severe SSADH-deficient mouse model following neonatal administration at escalating doses. AAV vector-mediated gene replacement conferred therapeutic benefit, including extended survival, reduced mortality, enhanced motor performance, and significant reductions in urinary GABA and GHB levels. The survival benefit was most evident at the high dose, suggesting the presence of an apparent therapeutic threshold for survival benefit. Vector genomes were distributed throughout the central nervous system and liver, with the robust restoration of SSADH expression in the central nervous system. These findings provide strong preclinical justification for the clinical translation of central nervous system-directed AAV vector gene therapy in this disorder.