Biochemical Society transactions
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Failure in the regulation of mTOR (mammalian target of rapamycin) appears to be critical to the pathogenesis of the inherited disorder tuberous sclerosis and the related lung disease LAM (lymphangioleiomyomatosis). Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1-TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents and antiproliferative agents in drug-eluting coronary artery stents. They also represent candidate therapies directed to the underlying molecular pathology in tuberous sclerosis and LAM. ⋯ An important, although variable, feature of the tuberous sclerosis phenotype is learning difficulty. Recent studies in mouse models carrying heterozygous Tsc2 mutations demonstrated improvement in memory and learning deficits following treatment with rapamycin. These promising pre-clinical and early human trials are being followed by larger-scale randomized control trials of mTOR inhibitors for treatment of renal, lung and brain manifestations of TSC1- and TSC2-associated disease.