Preclinical Testing of Splice Modulating Oligonucleotides Targeting SCN8A to Treat Dravet Syndrome

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 seizures are 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 NavchannelsNotablyintroducing an SCN A LOF mutation into a SCN A LOF DS mouse model willrescuethe DS phenotypeameliorating seizures and early deathThereforespecifically reducing SCN A mediated excitation should rebalance the deficit of inhibitory input caused by SCN A loss of function mutations and cause fewer adverse effects than sodium channel blockers which non selectively antagonize multiple NachannelsSCN A subunits are naturally alternatively spliced to produce a non functional isoformThuswe developed novel compounds called splice modulating oligonucleotidesSMOsthat direct SCN A pre mRNA splicing to produce less functional isoforms of SCN A proteinSMOs are a class of synthetic RNA based compounds that sterically block or weaken interactions between elements of the splice machinery and the premRNA with exceptional potencyspecificityand negligible off target effects at efficacious doses in CNSSCN A SMOs were designed in silico and refined for potency and specificity in vivo to identify two top SMO drug candidatesPreliminary testing of both candidate SMOs in a DS mouse model with an SCN A LOF mutation largely eliminated seizures during a critical period and robustly increased survivalFrom these two candidates a lead SCN A SMO will be selected to move forward into further pre clinical testingNon GLP toxicology and pharmacodynamics testing will be performed in rats by the same intrathecali tdelivery method expected to be used in clinical trialsThe single maximal tolerable doseMTDand no observed adverse effectsNOAELwill be determinedfollowed by assessment of MTD and NOAEL at multiple dosesup toweekly dosesand lastly studies to understand the duration of action at the MTD and NOAEL dosesAimAdditional testing will be performed in DS mice to establish the MTD and the minimally effective SMO doseMEDthat reduces seizuresimproves survivaland does not cause adverse motor effects or induce anxiety behaviors associated with SCN A knockdown in miceAimThese studies are designed to continue pre clinical testing in preparation for formal GLP toxicology studiesThe ultimate goal is to develop an SCN A SMO as potential therapeutic for the treatment of Dravet Syndrome Project NarrativeEpilepsies caused by mutations in a specific geneSCN Acause a severe childhood epilepsy called Dravet SyndromeDSwhich 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 deathThuswe have developed a novel compound that prevented seizure and death in a DS mouse model and we are moving forward with pre clinical testing in the current proposal towards GLP toxicology studies