Subtype Selective GABAA Receptor Modulators for the Treatment of Dravet Syndrome

PROJECT SUMMARY Dravet SyndromeDSis one of the most pharmacoresistant epilepsy syndromesInof patientsDS results from loss of function mutations in the Scn a gene which encodes brain voltage gated sodium channel type INaVEffective therapy for DS is extremely limitedThe current first line therapy for DS is a combination of Onficlobazamand valproic acidStiripentolSTPis often added for pharmacoresistant patients but is not an FDA approved treatmentUnfortunatelythis combination not only fails to provide complete seizure controlbut also causes serious adverse events in overof patientsBetter therapeutic strategies are urgently neededEncouraginglyrecent discoveries have unearthed a promising new pathway for treating this terrible diseaseAnimal studies in Scn aheterozygous knockout micea well established animal model of DShave established that spontaneous seizureshyperthermia induced seizuresand high rates of premature death are associated with reduced Gabraexpression in the forebrainGabraencodes the production of theprotein subunit of GABAARIntriguinglyclobazam and its metaboliteN desmethyl clobazamNDMChave modest selectivity in potentiatingcontaining GABAARsHigh doses of clobazammg kgeliminate hyperthermiainduced seizures in Scn aheterozygous knockout miceThis may partially explain why clobazam is effective in DS patients while other antiepileptics are notSTP not only increases NDMC levels through metabolic effects but is also selective forcontaining GABAARsAs a wholethis indicates that potentiating GABAARs containingand to a lesser extentmay play a significant role in controlling seizures in DS patientsNeuroCycle TherapeuticsIncNCTspecializes in the development ofsubtype selective GABAAR positive allosteric modulatorsThese compounds selectively potentiateandsubtypes but have minimal effect onsubtypes which are associated with side effects such as sedationdependencyataxiaand tolerance developmentIf effective in DS modelsthese selective compounds could deliver next generation treatment for DS that is effectivewell toleratedand useable long termIn preliminary studiesthese compounds are equally or more efficacious than diazepam in multiple in vivo anticonvulsant modelsThey also show efficacy in treatmentrefractory epileptic human cortical tissueThey display a significant margin of efficacy to side effectsand do not lose efficacy upon chronic dosingIn this Phase I SBIR applicationwe propose to test two compounds with differentiated receptor profiles in two animal models of DSFurthermorewe will perform a preliminary evaluation of these compoundsandapossuitability as preclinical candidatesIf Phase I objectives are metwe will apply to progress the best compound into a Phase II SBIR projectwhere additional pharmacologytoxicologyand pre clinical development will occur PROJECT SUMMARY Dravet syndromeDSis one of the most pharmacoresistant epilepsy syndromesCurrent first line combination therapy fails to provide complete seizure controland results in adverse events in overof patientsBetter therapeutic strategies are urgently neededNeuroCycle TherapeuticsIncNCTis developing subtype specific GABAA receptors as a novel therapeutic strategy for effectively treating DS with minimal side effects