Dravet Syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. In ~80% of patients, DS results from loss-of-function mutations in the Scn1a gene which encodes brain voltage-gated sodium channel type-I, NaV1.1. Effective therapy for DS is extremely limited. The current first-line therapy for DS is a combination of Onfi® (clobazam) and valproic acid. Stiripentol (STP) is often added for pharmacoresistant patients but is not an FDA approved treatment. Unfortunately, this combination not only fails to provide complete seizure control, but also causes serious adverse events in over 50% of patients. Better therapeutic strategies are urgently needed. Encouragingly, recent discoveries have unearthed a promising new pathway for treating this terrible disease. Animal studies in Scn1a+/- heterozygous knockout mice (a well-established animal model of DS) have established that spontaneous seizures, hyperthermia-induced seizures, and high rates of premature death are associated with reduced Gabra2 expression in the forebrain. Gabra2 encodes the production of the α2 protein subunit of GABAAR. Intriguingly, clobazam and its metabolite, N-desmethyl clobazam (NDMC), have modest selectivity in potentiating α2-containing GABAARs. High doses of clobazam (10 mg/kg) eliminate hyperthermia- induced seizures in Scn1a+/- heterozygous knockout mice. This may partially explain why clobazam is effective in DS patients while other antiepileptics are not. STP not only increases NDMC levels through metabolic effects but is also selective for α3-containing GABAARs. As a whole, this indicates that potentiating GABAARs containing α2, and to a lesser extent α3, may play a significant role in controlling seizures in DS patients. NeuroCycle Therapeutics, Inc. (NCT) specializes in the development of α2/α3 subtype-selective GABAAR positive allosteric modulators. These compounds selectively potentiate α2 and α3 subtypes but have minimal effect on α1 subtypes which are associated with side effects such as sedation, dependency, ataxia, and tolerance development. If effective in DS models, these selective compounds could deliver next-generation treatment for DS that is effective, well-tolerated, and useable long-term. In preliminary studies, these compounds are equally or more efficacious than diazepam in multiple in vivo anticonvulsant models. They also show efficacy in treatment- refractory epileptic human cortical tissue. They display a significant margin of efficacy to side-effects, and do not lose efficacy upon chronic dosing. In this Phase I SBIR application, we propose to test two compounds with differentiated receptor profiles in two animal models of DS. Furthermore, we will perform a preliminary evaluation of these compounds' suitability as preclinical candidates. If Phase I objectives are met, we will apply to progress the best compound into a Phase II SBIR project, where additional pharmacology, toxicology, and pre-clinical development will occur.
Public Health Relevance Statement: PROJECT SUMMARY Dravet syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. Current first-line combination therapy fails to provide complete seizure control, and results in adverse events in over 50% of patients. Better therapeutic strategies are urgently needed. NeuroCycle Therapeutics, Inc (NCT) is developing subtype-specific GABAA receptors as a novel therapeutic strategy for effectively treating DS with minimal side effects.
NIH Spending Category: Brain Disorders; Epilepsy; Intellectual and Developmental Disabilities (IDD); Neurodegenerative; Neurosciences; Orphan Drug; Pediatric; Rare Diseases
Project Terms: Adverse event; Affect; Age-Months; Agonist; Ames Assay; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Area Under Curve; Ataxia; autistic; Back; Benzodiazepines; Biological Assay; Body Temperature; Brain; Cardiotoxicity; Cessation of life; Chronic; Clinical; clinical predictors; clobazam; Combined Modality Therapy; comorbidity; Complex; Control Groups; cytotoxicity; Data; Dependence; Development; Diazepam; Disease; Dizziness; Dose; Dose-Limiting; dravet syndrome; Drug Kinetics; drug market; effective therapy; efficacy testing; Epilepsy; Evaluation; FDA approved; Frequencies; Gene Expression; Genes; genotoxicity; Grant; Human; Hyperthermia; Impaired cognition; in vivo; Incidence; Induced Hyperthermia; Injury; Knockout Mice; lead series; Live Birth; loss of function mutation; Medical; Memory impairment; Metabolic; Modeling; motor impairment; Mus; Mutation; next generation; novel; novel therapeutics; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Plasma; Play; positive allosteric modulator; pre-clinical; preclinical development; premature; Premature Mortality; Production; Prosencephalon; Protein Subunits; Quality of life; Rare Diseases; receptor; Refractory; Risk; Role; Sedation procedure; Seizures; Serious Adverse Event; side effect; Site; Sleep disturbances; Small Business Innovation Research Grant; Sodium Channel; Solubility; Sprague-Dawley Rats; Syndrome; Testing; Therapeutic; Tissues; Tonic - clonic seizures; Valproic Aci
