Soticlestat, a novel cholesterol 24‐hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice

Abstract

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.

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI):II. Drugs in more advanced clinical development

“…In Scn1a +/− mice (a model of Dravet syndrome), soticlestat reduced seizure burden, protected against hyperthermia‐induced seizures, and completely prevented sudden unexpected death in epilepsy (SUDEP; Figure 3A). No generalized tonic–clonic seizure events in soticlestat‐treated mice advanced to the most severe stages that include tonic hindlimb extension (Figure 3B), which is indicative of brainstem invasion and correlated with increased SUDEP risk 87 …”

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

“…There has also been a remarkable progress in screening for new treatments for Dravet syndrome, using both rodents (233,384,(549)(550)(551)(552)(553)(554)(555)(556)(557)(558) as well as high throughput studies in zebrafish (391,(559)(560)(561)(562)(563)(564). A noteworthy development has been the recent approval by the Food and Drug Administration of fenfluramine, a reuptake inhibitor of 5-OH-tryptamine, for the treatment of Dravet syndrome, based on evidence provided by both preclinical (560, 561) and clinical trials (230,(565)(566)(567)(568)(569).…”

Efficacy and safety of adjunctive antiseizure medications for dravet syndrome: A systematic review and network meta-analysis

“…Fenfluramine is also a positive regulator of the sigma-1 receptor ( Martin et al, 2020 ). Soticlestat is a cholesterol 24-hydroxylase inhibitor that can reduce the level of 24S-hydroxycholesterol (24HC) ( Hawkins et al, 2021 ; Koike et al, 2021 ). There is no direct head-to-head study on the efficacy and safety of these four drugs, and clinical decision-making largely depends on the availability of drugs in different regions, patient characteristics and needs, and personal preferences, making it difficult for clinicians to choose the best treatment method ( Zhang et al, 2022 ).…”