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 350 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-382, a specific GHB receptor antagonist with anti-sedative and anti-seizure properties. Two aims are proposed to test the hypothesis that NCS-382 provides neurotherapeutic efficacy (Aim #1), and with no significant systemic and cellular toxicity (Aim #2) 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-382 in patients with SSADHD.
Public Health Relevance Statement: 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-742 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.
Project Terms: 4-hydroxybutyric acid; 4-hydroxybutyric acid receptor; Address; Affinity; Aggressive behavior; aldehyde dehydrogenases; Aminobutyric Acids; Anxiety; Ataxia; base; Behavior; Binding; Biochemical; Biological Assay; Brain; Businesses; Cell Line; Cell Survival; Cellular biology; Cellular Metabolic Process; Chronic; Clinical; Clinical effectiveness; clinical efficacy; Clinical Research; Clinical Trials; combinatorial; commercialization; Communities; Coupled; Data; Developmental Delay Disorders; Diet; Disease; Dose; Drug Interactions; Ensure; Evaluation; Family; Foundations; Functional disorder; Future; Genes; Hepatocyte; Hepatotoxicity; Human; human disease; Hydroxybutyrates; improved; In Vitro; in vivo; Inherited; inhibitor/antagonist; Intellectual functioning disability; Knowledge; Laboratories; Letters; Measurement; Mediating; Memory; Metabolism; Microscopy; Morbidity - disease rate; Motor Activity; motor deficit; mouse model; Mus; Muscle hypotonia; Mutation; nerve stem cell; Neuraxis; neurobehavioral; Neuromodulator; neurophysiology; neuroprotection; neurotoxicity; novel; Nuclear Receptors; object recognition; Organ; Organelles; Outcome; Outcome Study; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; phase 2 study; Phenocopy; preclinical efficacy; preclinical evaluation; preclinical safety; preclinical study; Probability; Property; Rare Diseases; receptor; Reporter; Research; sedative; Seizures; Selective Serotonin Reuptake Inhibitor; SGS-742; Sleep disturbances; Staining method; Stains; Succinate-semialdehyde dehydrogenase deficiency; Succinates; succinic semialdehyde; Symptoms; systemic toxicity; Taurine; Testing; Therapeutic; Tissues; Toxic Actions; Toxic effect; valproate; Vigabatrin; Western Blotting
