Toward targeted treatments in tuberous sclerosis

ABSTRACT

Introduction. Tuberous Sclerosis Complex (TSC) is an autosomal-dominant disease caused by the loss of function of the heterodimeric complex hamartin/tuberin due to TSC1/TSC2 gene mutation. The consequent abnormal activation of mammalian target of rapamycin (mTOR), a serine threonine kinase regulating cellular growth, metabolism and proliferation, is responsible for the structural and functional abnormalities observed in TSC. mTOR inhibitors are a class of drugs specifically targeting the mTOR pathway with promising benefits as a specific targeted treatment of the disease.

Areas covered. We have reviewed the literature focusing on the role of mTOR inhibitors in treating TSC-related conditions. They are currently approved for subependymal giant cell astrocytomas, renal angiomyolipomas and more recently for lymphangioleiomyomatosis, but a promising role has been shown also in the other clinical manifestation characteristics of TSC, such as cardiac rhabdomyomas, facial angiofibromas and epilepsy.

Expert opinion. mTOR inhibition is considered a disease-modifying therapy and the best approach to prevent the progress of the natural history of the disease. For the first time we have the possibility not only to use a biologically targeted treatment, but also to address different manifestations at the same time, thus significantly improving the therapeutic outlook in this complex disease.

KEYWORDS:

• Everolimus
• mTOR
• mTOR inhibitors
• rapamycin
• treatment
• tuberous sclerosis complex

Article highlights

• mTOR inhibitors are increasingly recognized as a biologically targeted disease modifying therapy in TSC.

• mTOR inhibitors are considered as a systemic therapy, with a good efficacy on SEGA, AML and LAM, and with promising results on epilepsy, cardiac rhabdomyomas and skin lesions.

• mTOR inhibitors are overall well tolerated, being usually associated with mild and self-limited adverse events.

• mTOR inhibitors are being increasingly used during infancy, showing an acceptable tolerability profile as well as good efficacy.

• Some open questions on mTOR inhibitors remain, such as the optimal dosing strategy, as well as the optimal time for initiating therapy.

• Combining mTOR inhibitors with other classes of drugs might help to obtain more complete responses in higher rates of patients.

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Declaration of interest

R Moavero and P Curatolo received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391 (www.epistop.eu). The authors have no other 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.