Long-term use of mTORC1 inhibitors in tuberous sclerosis complex associated neurological aspects

Abstract

ABSTRACT Introduction Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease caused by mutation in TSC1/2 genes, leading to the hyperactivation of the mammalian/mechanistic target of Rapamycin complex 1 (mTORC1) pathway. Until recently, treatment for TSC-related manifestations was merely symptomatic, but in the last years allosteric mTORC1 inhibitors, such as Everolimus, proved effective in managing several lesions and symptoms. Areas covered MedLine was performed focusing on years 2010-2020. Long-term studies show that Everolimus maintains its efficacy over time, and that benefits might appear for the first time even months after starting treatment. Tolerability profiles reveal no unexpected toxicity, with adverse events decreasing over time. Analysis of tolerability in younger children didn’t reveal any effect on growth and puberty. Expert opinion mTORC1 inhibitors offer a targeted and systemic approach to TSC, but exact timing of initiation still remains a major issue. Another gap to be filled is the duration of treatment, since manifestations might recur after withdrawal, and alternative dosage schemes might be proposed. mTORC1 inhibitors revolutionized the therapeutic paradigm in TSC, however there is still a long way to go, since a lot of questions still remain unanswered and future studies are necessary to find a better cure.