Preclinical Evaluation of an SCN8A-directed Splice Modulating Oligonucleotide to Treat Dravet Syndrome

Project Summary Abstract Dravet Spectrum disorders resulting from SCN A loss of functionLOFmutations include febrile seizuresgeneralized epilepsy with febrile seizure plusGEFSand Dravet SyndromeDSin order of severityDS symptoms begin in infancy and lead to progressive developmental and behavioral impairments along with characteristic recurrent and varied seizuresIn many patientsseizures are resistant to currently available antiepileptic drugs and uncontrolled seizure activity is associated with an increased incidence of SUDEPsudden unexplained death in epilepsyThusthere is a significant and urgent need for the development of novel drug therapiesSCN A containing Navchannels functionally oppose the related SCN A containing NavchannelsWe have developed a novel therapeutic oligonucleotide candidateLSP SCN Athat works by reducing levels of SCN A by directing its splicing to a non functional isoformLSP SCN A greatly reduces seizures and increases lifespan in a mouse DS modelThe goals of the Phaseportion of the study will be to perform neurophysiological characterization of LSPSCN A in DS mice by cellular electrophysiology and video EEGIn the Phasecomponentwe will perform additional dose range studies for LSP SCN A in DS miceconfirm splicing activity of LSP SCN A in human cellsand generate a PD lot of the LSP SCN A SMO for non GLP dose finding studies in juvenile rats and primates in preparation for formal GLP toxicology studiesWe will also prepare for and conduct the pre IND meeting with the FDAThe ultimate goal of our company is to fully develop LSP SCN A as a therapeutic to treat DS Project NarrativeMutations the SCN A gene are responsible for a catastrophic epilepsy called Dravet SyndromeDSwhich starts in infancy or early childhood and often does not respond to currently available anti seizure drugsAlong with severe seizureschildren with DS have developmental and learning difficulties and increase risk for epilepsy related deathWe have developed a novel compound to counterbalance the effects of SCN A mutations which prevents seizure and death in a DS mouse model and are performing additional pre clinical testing and optimization in the current proposal in final preparation for formal GLP toxicology studies