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

Autor: Hawkins NA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Jurado M; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Thaxton TT; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Duarte SE; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Barse L; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA., Tatsukawa T; Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Japan., Yamakawa K; Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Japan., Nishi T; Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Ltd, Fujisawa, Japan., Kondo S; Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Ltd, Fujisawa, Japan., Miyamoto M; Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Ltd, Fujisawa, Japan., Abrahams BS; Ovid Therapeutics, New York, New York, USA., During MJ; Ovid Therapeutics, New York, New York, USA., Kearney JA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2021 Nov; Vol. 62 (11), pp. 2845-2857. Date of Electronic Publication: 2021 Sep 12.
DOI: 10.1111/epi.17062
Abstrakt: 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.
(© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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