Dravet syndrome (DS) is a severe and progressive genetic epilepsy characterized by frequent, prolonged, and refractory seizures, intellectual disability, and a high risk of sudden unexpected death in epilepsy. Approximately 85% of DS cases are caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene which encodes the voltage-gated sodium channel α subunit, NaV1.1. STK-001 is an investigational antisense oligonucleotide treatment using a unique platform, Targeted Augmentation of Nuclear Gene Output (TANGO), that exploits naturally occurring nonproductive splicing events to increase NaV1.1 protein expression. STK-001 may be the first precision medicine approach for DS. This clinical study aims to primarily assess the safety, tolerability, and pharmacokinetics of intrathecally administered STK-001. Secondary objectives aim to evaluate the effect of STK-001 on convulsive seizure frequency, overall clinical status and quality of life in DS patients. This phase 1/2a open-label single and multiple ascending dose study includes patients aged 2-18 years with disease onset prior to 12 months of age with recurrent seizures and genetically confirmed SCN1A variant. Each dose cohort enrolls up to 4 patients, with an option to dose up to 6 additional patients per cohort for safety evaluation. Study design includes a 4-week observation period evaluating seizure frequency, a treatment period in which all patients receive STK-001, and a 6-month follow-up period following the last dose of study drug. Adverse events are monitored throughout the study. Plasma and CSF are collected at multiple timepoints. Patients keep seizure and sleep diaries during the study. This study will provide insight into the safety, tolerability, and pharmacokinetic profile of ascending doses of STK-001 in DS patients. The impact of STK-001 on convulsive seizure frequency and quality of life may indicate the initial clinical effect of the individual doses. STK-001 has the potential to be the first disease-modifying therapy to address the genetic cause of DS by restoring physiological NaV1.1 levels and reducing both occurrence of seizures and significant non-seizure comorbidities. The dose implications of this study may better inform future clinical trials on the appropriate and effective dosing for efficacy measures. 

 
Funding: Sponsored by Stoke Therapeutics