Journal
EPILEPSIA
Volume 62, Issue 11, Pages 2845-2857Publisher
WILEY
DOI: 10.1111/epi.17062
Keywords
anticonvulsants; cholesterol 24-hydroxylase; epilepsy; Nav1; 1 voltage-gated sodium channel
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This study demonstrates the therapeutic potential of the novel compound soticlestat, a CH24H inhibitor, in improving Dravet-like phenotypes in mice by reducing seizure burden, protecting against hyperthermia-induced seizures, and completely preventing SUDEP. Video-electroencephalography analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures in the preclinical model.
Objective Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a(+/-)) recapitulates several core phenotypes, including temperature-dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a(+/-) mice exhibit a similar clinical response to standard anticonvulsants. Cholesterol 24-hydroxlase (CH24H) is a brain-specific enzyme responsible for cholesterol catabolism. Recent research has indicated the therapeutic potential of CH24H inhibition for diseases associated with neural excitation, including seizures. Methods In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a(+/-) mice to investigate its ability to improve Dravet-like phenotypes in this preclinical model. Results Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a(+/-) mice. Video-electroencephalography (EEG) analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures. Significance This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.
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