Rationale: Dravet Syndrome (DS) is the most common genetic developmental and epileptic encephalopathy (DEE), caused by pathogenic loss-of-function variants in the voltage-gated sodium channel gene SCN1A. Patients with DS present with prolonged febrile seizures in the first year of life, followed by the development of multiple intractable seizure types, a substantially increased risk for sudden unexpected death (SUDEP), and cognitive and behavioral impairments. Despite the availability of several newer medications, seizures remain medically refractory for many patients with DS, underscoring the need to explore additional therapeutic mechanisms.
4-phenylbutyrate (PBA) is an FDA approved compound for the treatment of urea cycle disorders. This compound is also known to be a chemical chaperone, hypothesized to stabilize mutant protein in the endoplasmic reticulum, allowing it to reach the cell surface.
1,2 This mechanism is intriguing as a potential therapeutic target in genetic epilepsies caused by haploinsufficiency to potentially improve trafficking of functional proteins to the cell surface. We therefore sought to explore PBA as a potential therapeutic agent in a mouse model of DS.
Methods: 129S6.Scn1a
+/- mice (gift from Drs. Lori Isom and Jennifer Kearney) were bred with C57BL/6J (Jax #00064) to create F1 offspring. Scn1a
+/- offspring received daily intraperitoneal injections of 400mg/kg PBA or an equal volume of 0.9% normal saline from P18-P40. Weights were recorded daily and litters were monitored for spontaneous deaths. At P40-42, surviving mice were exposed to hyperthermia to induce seizures. Thermal seizure induction was video recorded and scored by an observer who was blinded to treatment groups. Seizure threshold temperature and seizure severity were evaluated.
Results: Spontaneous death (SUDEP) occurred in two of five (40%) saline treated mice compared to zero of six (0%) of PBA treated mice during the study period. Of the surviving mice, convulsive (Racine grade 5) seizures provoked by hyperthermia were observed in one of three (33%) saline-treated mice, while no hyperthermia-provoked seizures were observed in any of the 6 PBA treated mice. Combining this preliminary data, three of five control mice had an observed significant seizure event during the study period compared to zero of six PBA treated mice (p < 0.05, Mantel-Cox test).