A preterm infant with a genetic disease had the frequency of her seizures reduced by more than half after Ludwig-Maximilians-Universität München-led researchers treated her with elsunersen, an antisense oligonucleotide that specifically targets her condition. The drug is still in development, so this was done under expanded access.
The study appears in Nature Medicine. The lead author is Matias Wagner, Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics and Comprehensive Epilepsy Center, Munich University Center for Children with Medical and Developmental Complexity.
The baby was diagnosed with early-onset SCN2A developmental and epileptic encephalopathy (DEE). She did not respond to approved epilepsy medications.
She was initially having 20 to 25 seizures per hour, until seven weeks after birth when elsunersen was administered. That rate declined to five to seven seizures per hour following repeated intrathecal dosing with the drug, and the effects lasted as long as she was treated. Elsunersen treatment was safe, with no severe or serious adverse events reported after 19 intrathecal administrations over 20 months.
According to the Epilepsy Foundation, there are almost 1,000 different genes that have been established to play a role in epilepsy. The symptoms of genetic epilepsies are highly variable, depending on which gene is involved. It is often not possible to pinpoint the exact gene involved based on the patient’s symptoms alone.
Early-onset SCN2A DDE encephalopathy is caused by gain-of-function variants. It is a rare monogenic disorder characterized by early-onset ( Variants in SCN2A that cause loss of function are associated with an encephalopathy characterized by onset of seizures at typically more than 3 months of age or with autistic features without seizures. Variants that cause biophysical gain-of-function (GoF) changes can cause a distinct spectrum of disorders including a severe form of SCN2A-DEE where seizures are often difficult to control with conventional antiseizure medications.
Antisense oligonucleotides have emerged as a promising class of therapeutic interventions for a range of genetic disorders. It has also been shown in vitro and in a Scn2a GoF mouse model that treatment with a mouse-specific gapmer ASO could safely reduce mRNA levels and seizure burden, paving the way for clinical development in patients with SCN2A GoF-associated DEE.
Elsunersen is a gapmer antisense oligonucleotide targeting SCN2A mRNA being developed by Praxis Precision Medicines. Praxis recently announced that it has finalized the registrational trial design for its latest study of elsunersen – EMBRAVE3, which will be “a global, 24-week, double-blind, sham-procedure controlled study, with approximately 40 early-onset SCN2A-DEE patients, and is anticipated to start enrolling patients by mid-year 2025.”
The researchers write, “These data provide preliminary insights on the safety and efficacy of elsunersen in a preterm infant.”
