Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.
Ann Clin Transl Neurol
; 10(10): 1790-1801, 2023 10.
Article
en En
| MEDLINE
| ID: mdl-37545094
ABSTRACT
OBJECTIVE:
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy.METHODS:
In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1.RESULTS:
Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development.INTERPRETATION:
Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Esclerosis Tuberosa
/
Epilepsia
Límite:
Animals
Idioma:
En
Revista:
Ann Clin Transl Neurol
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos