mTOR-therapy and targeted treatment opportunities in mTOR-related epilepsies associated with cortical malformations.

Abstract

Dysregulation of the mTOR pathway is now well documented in several neurodevelopmental disorders associated with epilepsy. Mutations of mTOR pathway genes are involved in tuberous sclerosis complex (TSC) as well as in a range of cortical malformations from hemimegalencephaly (HME) to type II focal cortical dysplasia (FCD II), leading to the concept of "mTORopathies" (mTOR pathway-related malformations). This suggests that mTOR inhibitors (notably rapamycin (sirolimus), and everolimus) could be used as antiseizure medication. In this review, we provide an overview of pharmacological treatments targeting the mTOR pathway for epilepsy based on lectures from the ILAE French Chapter meeting in October 2022 in Grenoble. There is strong preclinical evidence for the antiseizure effects of mTOR inhibitors in TSC and cortical malformation mouse models. There are also open studies on the antiseizure effects of mTOR inhibitors, as well as one phase III study showing the antiseizure effect of everolimus in TSC patients. Finally, we discuss to which extent mTOR inhibitors might have properties beyond the antiseizure effect on associated neuropsychiatric comorbidities. We also discuss a new way of treatment on the mTOR pathways.

• Authors: S Auvin, S Baulac
• Journal: Revue neurologique (Rev Neurol (Paris)) Vol. 179 Issue 4 Pg. 337-344 (Apr 2023) ISSN: 0035-3787 [Print] France
• PMID: 36906459 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Chemical References

• MTOR Inhibitors
• Everolimus
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Mice
• MTOR Inhibitors
• Everolimus (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (genetics, metabolism, therapeutic use)
• Epilepsy (etiology, complications)
• Malformations of Cortical Development, Group I (complications, drug therapy)
• Sirolimus (therapeutic use)