Preclinical Evaluation of NCS-382 in Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD)

SUMMARY Succinic semialdehyde dehydrogenase deficiency SSHDHD is an autosomal recessively inherited ultra rare disorder caused by accumulation of two neuromodulators in tissues and biofluids hydroxybutyrate GHB and aminobutyric acid GABA It is believed that the toxic action of GABA and GHB is mediated by their action on specific receptors widely distributed in the brain and other organs the GABA and GHB receptors The disorder has been identified in approximately families and is associated with severe morbidity including developmental delay hypotonia intellectual disability ataxia seizures and hyperkinetic behavior aggression and sleep disturbances There is no cure and available treatments are primarily symptomatic The clinical efficacy of GABA receptor antagonism is being evaluated in an ongoing clinical trial However to date no systematic effort has been made to characterize how GHBR antagonism might mitigate the impact of elevated GHB concentration and improve the clinical presentation of the disease Our project addresses this gap with preclinical safety and efficacy studies of NCS a specific GHB receptor antagonist with anti sedative and anti seizure properties Two aims are proposed to test the hypothesis that NCS provides neurotherapeutic efficacy Aim and with no significant systemic and cellular toxicity Aim using a well established mouse model of the human disease the SSADH deficient mouse and relevant cell lines in culture These aims are supported by preliminary data that demonstrate experimental feasibility and the probability of a successful outcome of our proposed research strategy The proposed studies will capitalize on the decades long expertise of the academic partner in SSADHD research and the focus of the Small Business Concern on developing effective cures for patients with SSADHD The completion of the aims will provide the necessary foundation for Phase II studies IND applications and commercialization plans and thus will be critical to the projected use of NCS in patients with SSADHD NARRATIVE Inherited succinic semialdehyde dehydrogenase deficiency SSADHD the most common disorder of GABA metabolism is unique in the accumulation of the neuromodulators GABA and gamma hydroxybutyric acid GHB The pleiotropic pathophysiology of SSADHD implies that combinatorial therapeutic approaches will be required to achieve incremental phenotypic improvements Preclinical studies of the GABAB receptor antagonist SGS in mice with SSADHD were foundational in implementing the first targeted clinical trial However until now no effort has been made to characterize the therapeutic relevance of GHB receptor antagonism The proposed project addresses this gap of knowledge a gap which has been a critical barrier to progress in finding a successful treatment for SSADHD