Novel genetic tools to model functional enzyme restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD)

SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the aldh5a1 gene), an enzyme essential for breaking down the inhibitory neurotransmitter γ -aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA results in broad spectrum encephalopathy including developmental delay, ataxia, seizures and a risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy (ERT) or aldh5a1 gene transfer increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable cure for SSADHD. However, before testing SSADH restoration therapy in patients, we must consider its safety and feasibility in context of the unique SSADHD pathophysiology. Specifically, a profound use-dependent down-regulation of GABA A receptors in SSADHD indicates a risk that sudden SSADH restoration might diminish GABAergic tone and provoke seizures. Such risk may be mitigated by gradual, rather than abrupt, SSADH restoration, or by restoration that is confined to critical cell types and brain regions. We therefore describe early work to construct a novel SSADHD mouse model that allows ‘on-demand’ SSADH restoration for the systematic investigation of the rate, timing and cell-specific parameters of SSADH-restoring therapies. We aim to understand the clinical readiness of specific SSADH restoration protocols on brain physiology for purposes of accelerating the bench to bed-side development of ERT or gene therapy for SSADHD patients.