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

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.

KEYWORDS:

• Epilepsy
• everolimus
• long-term outcome
• mTOR
• mTORC1 inhibitors
• rapamycin
• subependymal giant cell astrocytoma
• tuberous Sclerosis complex

Article highlights

• mTORC1 inhibitors present a pathogenic and systemic effect on TSC-related manifestations.

• Everolimus proved to be effective and safe in SEGA and epilepsy.

• mTORC1 inhibitors also proved their efficacy in other systemic manifestations of TSC, such as renal angiomyolipomas, pulmonary lymphangioleyomiomatosis, and facial angiofibromas.

• Everolimus maintains its efficacy over time, and benefits might also appear for the first time even months after starting treatment.

• No unexpected toxicity is encountered with long-term treatment, and adverse events decrease over time.

• Analysis of tolerability in younger children didn’t reveal any effect on growth and puberty.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.