Is mTOR inhibition a systemic treatment for tuberous sclerosis?

Abstract

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.

Mechanistic Target of Rapamycin (mTOR) in Tuberous Sclerosis Complex-Associated Epilepsy

“…In a critically ill 10-year-old boy with TSC and pharmacoresistant epilepsy, everolimus treatment resulted in complete cessation of epileptic seizures within the first 6 weeks. 43 Additionally, everolimus treatment in a 20-year-old girl with SEGAs and angiomyolipomas resulted in a significant reduction in seizure frequency and 49 Recently, the efficacy and side effects of rapamycin or sirolimus were evaluated in an open-label, single-center case series of seven patients with TSC and pharmacoresistant epilepsy. 50 Seizure freedom was obtained in two patients for at least 6 months and in one patient for 12 months, followed by >90% reduction in seizures thereafter.…”

Everolimus in Immunosuppressive Treatment After Kidney Transplantation in a Patient With Tuberous Sclerosis: Case Report

“…In some clinical trials, the doses of 5 mg or 10 mg daily or 30 mg, 50 mg, or 70 mg weekly were used. In the others, the dose was titrated to achieve serum concentrations of 3 to 5 ng/mL, 5 to 10 ng/mL, and up to 5 to 15 ng/mL [20,21,24]; moreover, this is not compatible with dosing recommendations in transplant recipients and might potentially limit expected benefits in TSC patients. The rapamycin data show that "the immunosuppressive dosage" after kidney transplantation can be beneficial to TSC manifestations [13e18].…”

Targeted therapy for tuberous sclerosis complex

“…Всех ученых и врачей, занимающихся туберозным склерозом, волнует во-прос: является ли эверолимус системным препаратом? [13]. Да, мы знаем, что он эффективен при субэпен-димальных гигантоклеточных астроцитомах, ангио-миолипомах и кожных проявлениях.…”

“…Ингибиторы mTOR в эксперимен-тальных моделях эпилепсии, не связанной с тубероз-ным склерозом, дают противосудорожный эффект, но, возможно, он продолжается только до тех пор, пока препарат применяется [13]. Может ли эвероли-мус предотвращать эпилептогенез при туберозном склерозе -вопрос пока открытый.…”