Authors :
Presenting Author: Joseph Sullivan, MD – Weill Institute for Neurosciences and Benioff Children’s Hospital, University of California San Francisco
Ingrid Scheffer, AO MBBS PhD FRACP FAES FAA FRS – Epilepsy Research Centre and Royal Children’s Hospital, The University of Melbourne, Austin Health, Florey and Murdoch Children’s Research Institutes
Katherine Howell, MBBS, PhD – The University of Melbourne, Royal Children’s Hospital, Neuroscience Research Group, Murdoch Children's Research Institute
M. Scott Perry, MD – Cook Children’s Physician Network
Archana Desurkar, MD – Sheffield Children's Hospital
J. Helen Cross, M.B., Ch.B., PhD – University College London NIHR BRC Great Ormond Street Institute of Child Health
Amy McTague, MBChB, PhD – UCL Great Ormond Street Hospital for Children
Andreas Brunklaus, M.D. – University of Glasgow
Nalin Gupta, MD, PhD – University of California at San Francisco
Kurtis Auguste, MD – University of California at San Francisco
Alison Wray, MD – The University of Melbourne, Royal Children’s Hospital
Daniel Hansen, MD – Cook Children's Medical Center
Shungu Ushewokunze, MB CHB, MRCS FRCS – Sheffield Children's Hospital
Kristian Aquilina, FRCS – Great Ormond Street Hospital for Children
Roddy O'Kane, MD – University of Glasgow
Stéphane Auvin, MD, PhD – Center for rare epilepsies, Pediatric Neurology Dpt, Robert-Debré Hospital, Paris, France
Dennis Lal, PhD – Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Colin Roberts, M.D. – Oregon Health & Science University, Doernbecher Children’s Hospital
Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia
Sameer Zuberi, ChB, MD, FRCP, FRCPCH – University of Glasgow
Alexander King, BS – Encoded Therapeutics
Shawn Jones, BS – Encoded Therapeutics
Sarah Christensen, BS – Encoded Therapeutics
Jacqueline Gofshteyn, MD – Encoded Therapeutics
Maria Candida Vila, PhD, PharmD – Encoded Therapeutics
Norman Huang, PhD – Encoded Therapeutics
Emma James, PhD MFPM (Hon) – Encoded Therapeutics
Stephanie Tagliatela, BA – Encoded Therapeutics
Salvador Rico, MD, PhD – Encoded Therapeutics
Rationale:
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy (DEE) characterized by drug-resistant seizures and slowing in neurodevelopment from early in life. More than 90% of cases are caused by heterozygous, loss-of-function variants in SCN1A, which encodes the alpha-1 subunit of the voltage-gated sodium channel NaV1.1. ETX101 is a potentially one-time, AAV-based gene regulation therapy for DS, designed to address the core cellular and genetic dysfunction by upregulating Nav1.1 protein expression preferentially in GABAergic interneurons.1
1Tanenhaus A, et al. Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates. Hum Gene Ther. 2022 Jun;33(11-12):579-597.
Methods:
POLARIS is an ongoing Phase 1/2 program comprising three open-label, dose-escalation studies—ENDEAVOR (USA, NCT05419492), WAYFINDER (AUS, NCT06112275) and EXPEDITION (UK, NCT06283212). Eligible participants are 6 months to 7 years of age, have a predicted loss-of-function, pathogenic or likely pathogenic SCN1A variant, experienced their first seizure between the ages of 3 and 15 months, and are receiving standard of care anti-seizure medications. Ascending dose levels of ETX101 are assessed following a single intracerebroventricular (ICV) administration on Day 1 (n=3–4 per dose cohort).
Results:
As of June 1, 2025, ETX101 has been administered in 11 participants with follow-up for up to 58 weeks. To date, no treatment-related serious adverse events or dose-limiting toxicities have been reported. Early efficacy data show dose-dependent reductions in seizure burden and use of rescue medications, and an increase in seizure-free days. Following a single ICV infusion of ETX101, a median reduction of 87% (range: 47%–90%) in monthly countable seizure frequency (MCSF) from baseline was observed at the highest dose tested, across the evaluable observation period (Week 5 to at least Week 12 post-dosing at data cut-off). Dose escalation is ongoing. Additional safety and seizure data will be presented.
Conclusions:
Preliminary results from the POLARIS program demonstrate that ascending dose levels of ETX101 have been well-tolerated with no safety concerns related to study drug. Dose-dependent anti-seizure effects highlight the promising therapeutic potential of ETX101 and support continued development to establish its efficacy and long-term impact. Notably, this research represents the first clinical data for an investigational one-time, cell-type selective, gene regulation therapy, and the first potential one-time, disease-modifying treatment for DS.
Funding: Encoded Therapeutics