Early Use of mTOR Inhibitors in Tuberous Sclerosis: Current State and Plan for a Prospective Clinical Trial of Early Prophylactic mTOR Inhibitor Treatment (PROTECT)

Background/Purpose: Tuberous sclerosis (TSC) is a multisystem disorder with high risk for autism spectrum disorders and intellectual disability. Causes and potential intervention strategies for the highly variable symptoms are poorly understood. It is not known whether early inhibition of the accelerated mTOR signaling pathway has long-term beneficial effects on the development of affected children.

Methods: Based on data from a multicenter retrospective study of children who received early mTOR inhibitors, we summarize the current status on the benefit of mTOR inhibitors in TSC and present the rationale and plan for a prospective clinical trial of prophylactic mTOR inhibitor treatment in children with TSC before 4 months of age.

Results: The results from the German cohort of infants and from international published data show that early use of mTOR inhibitors is safe and has good effects on various symptoms. Putative beneficial effects from mTOR inhibitors on development are supported by positive outcome reports in TSC mouse models. Despite the availability of targeted modulators of the mTOR pathway and evidence from animal models, no conclusions can be drawn regarding putative effects of mTOR inhibitors on long-term neurological development in children and controlled studies on the prophylactic use of mTOR inhibitors are lacking.

Conclusion: mTOR inhibitors can be used with an acceptable safety profile in infants and even neonates with TSC. The multicenter randomized trial of prophylactic use of sirolimus in infants with TSC will allow, for the first time, to investigate the long-term benefit on developmental outcome.

Publication History

Article published online:
28 October 2021