Investigating the use of mTOR inhibitors in Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a genetic disease caused by variants in the tumour suppressor genes TSC1 and TSC2, located on chromosomes 9 and 16. (1, 2) Approximately 70% of cases are sporadic. The birth incidence has been estimated as 1 in 5,800 per year. The protein products of TSC1 and TSC2 (hamartin and tuberin) function together within the cell and have an inhibitory effect on the mammalian target of rapamycin (mTOR), a protein kinase that influences cell growth. Variant in either TSC1 or TSC2 leads to over-activation of the mTOR pathway and relatively uncontrolled cell growth. This, in turn, causes growth of benign tumours in various organs such as the brain, kidneys, skin, heart and lungs. (3-5) Artificial inhibition of mTOR is a therapeutic option in patients with TSC. The mTOR inhibitor currently being used in TSC (everolimus) has significant side-effects. Metformin, which also inhibits mTOR and has a relatively benign side-effect profile, has never before been studied in TSC patients. The aim of this project was firstly to investigate the impact of TSC on patients’ lives and then to investigate the impact of mTOR inhibition via novel methods, and their effect on patients with TSC. Initially I studied a large cohort of TSC patients to identify the morbidity of TSC and causes of early mortality. Subsequently I investigated the impact of TSC on quality of life. This was the first study to look at the impact of TSC on patients’ physical, emotional, social and school functioning. The final part of the thesis investigates the effect of mTOR inhibition, delivered in novel ways, on TSC related complications. Firstly, I studied the safety and effectiveness of using topical rapamycin in patients with facial angiofibromatosis. Secondly, I conducted a multi-centre double blind randomised placebo controlled trial of metformin in patients with TSC. Specifically, I investigated the safety and effectiveness of metformin on TSC-related lesions (renal angiomyolipomas, and cerebral subependymal giant cell astrocytomas), epilepsy, quality of life, and cognition.