SBIR-STTR Award

Direct to Phase II

Dravet Spectrum disorders resulting from SCN1A loss-of-function (LOF) mutations include febrile seizures,generalized epilepsy with febrile seizure plus (GEFS+), and Dravet Syndrome (DS) in order of severity. DSsymptoms begin in infancy and lead to progressive developmental and behavioral impairments along withcharacteristic recurrent and varied seizures. In many patients, seizures are resistant to currently availableantiepileptic drugs and uncontrolled seizure activity is associated with an increased incidence of SUDEP(sudden unexplained death in epilepsy). Thus, there is a significant and urgent need for the development ofnovel drug therapies.SCN1A-containing Nav1.1 channels functionally oppose the related SCN8A-containing Nav1.6 channels. Wehave developed a novel therapeutic oligonucleotide candidate, LSP-SCN8A, that works by reducing levels ofSCN8A by directing its splicing to a non-functional isoform. LSP-SCN8A greatly reduces seizures andincreases lifespan in a mouse DS model.The goals of the Phase 1 portion of the study will be to perform neurophysiological characterization of LSP-SCN8A in DS mice by cellular electrophysiology and video-EEG. In the Phase 2 component, we will performadditional dose-range studies for LSP-SCN8A in DS mice, confirm splicing activity of LSP-SCN8A in humancells, and generate a PD lot of the LSP-SCN8A SMO for non-GLP dose-finding studies in juvenile rats andprimates in preparation for formal GLP-toxicology studies. We will also prepare for and conduct the pre-INDmeeting with the FDA. The ultimate goal of our company is to fully develop LSP-SCN8A as a therapeutic totreat DS.

Public Health Relevance Statement:


Project narrative:
Mutations the SCN1A gene are responsible for a catastrophic epilepsy called Dravet Syndrome (DS) which starts in infancy or early childhood and often does not respond to currently available anti-seizure drugs. Along with severe seizures, children with DS have developmental and learning difficulties and increase risk for epilepsy-related death. We have developed a novel compound to counterbalance the effects of SCN1A 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.

Project Terms:
<21+ years old><0-11 years old>