Antisense oligonucleotide treatment in a preterm infant with early-onset SCN2A developmental and epileptic encephalopathy
Early-onset SCN2A developmental and epileptic encephalopathy is caused by SCN2A gain-of-function variants. Here we describe the clinical experience with intrathecally administered elsunersen, a gapmer antisense oligonucleotide targeting SCN2A, in a female preterm infant with early-onset SCN2A developmental and epileptic encephalopathy, in an expanded access program. Before elsunersen treatement, the patient was in status epilepticus for 7 weeks with a seizure frequency of 20-25 per hour. Voltage-clamp experiments confirmed impaired channel inactivation and increased persistent current consistent with a gain-of-function mechanism. Elsunersen treatment demonstrated a favorable safety profile with no severe or serious adverse events reported after 19 intrathecal administrations over 20 months. After administration in combination with sodium channel blockers, status epilepticus was interrupted intermittently and ultimately ceased after continued dosing. A >60% reduction in seizure frequency corresponding to five to seven seizures per hour was observed, which has been sustained during follow-up until the age of 22 months. These data provide preliminary insights on the safety and efficacy of elsunersen in a preterm infant. Additional investigation on the benefits of elsunersen in clinical trials is warranted.
Authors
- Walid Fazeli (ORCID: https://orcid.org/0000-0002-9425-5535)
- Christoph Hübener
- F. Heer
- Claudia Nußbaum (ORCID: https://orcid.org/0000-0003-4414-6717)
- Florian Heinen (ORCID: https://orcid.org/0000-0002-3872-6136)
- Henry Jacotin
- Silvana Frizzo
- Moritz Tacke (ORCID: https://orcid.org/0000-0002-7192-5671)
- Markus Wolff (ORCID: https://orcid.org/0000-0001-5640-0888)
- Géza Berecki (ORCID: https://orcid.org/0000-0002-8664-6325)
- Corinna Siegel
- Ingo Borggraefe (ORCID: https://orcid.org/0000-0002-8484-5945)
- Matias Wagner (ORCID: https://orcid.org/0000-0002-4454-8823)
- Marcio Souza
- Steven Petrou (ORCID: https://orcid.org/0000-0002-4960-6375)
- Andreas W. Flemmer (ORCID: https://orcid.org/0000-0002-4601-0314)
- Brian D. Spar
- Marco Paolini (ORCID: https://orcid.org/0000-0001-5731-5925)
- WILLIAM G. MOTEL
- Martin Staudt (ORCID: https://orcid.org/0009-0008-8210-5215)
- Christoph A. Klein (ORCID: https://orcid.org/0000-0003-0956-0445)
- Sophia Stöcklein
- Robert Horton
Institutions
- Florey Institute of Neuroscience and Mental Health (AU)
- University Hospital Bonn (DE)
- Helmholtz Zentrum München (DE)
- Praxis (United States) (US)
- Precision for Medicine (United States) (US)
- Max Planck Institute of Neurobiology (DE)
- Swiss Epilepsy Center (CH)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1038/s41591-025-03656-0
- Citations
- 22
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 17.73
Funders
- Gemeinnützige Hertie-Stiftung
- Ludwig-Maximilians-Universität München