Abstracts

Rationale: TSC is a potentially devastating disorder characterized by hamartoma formation in multiple organ systems and associated disabling neurological disorders including epilepsy, mental retardation, and autism. TSC lesions occur throughout the body including the kidney (angiomyolipomas), lungs (lymphangiomyomatosis), and brain (cortical tubers and subependymal giant-cell astrocytomas [SEGAs]). Epilepsy occurs in 80%-90% of patients with TSC, and seizures may be severe and often difficult to control with available antiepileptic drugs. The epileptogenic source is presumed to be neuronal tubers, cerebral cortex abnormalities present in 90% of patients with TSC. Neurosurgical resection, corpus callosotomy, and vagus nerve stimulation with their associated complications and comorbidities are the current standard treatments for intractable epilepsy associated with TSC; no effective alternatives have been identified. TSC is caused by mutations in 1 of 2 genes, TSC1 or TSC2. The protein products of these genes, hamartin and tuberin, form a heterodimer to negatively regulate mTOR, a key intracellular kinase regulating cell growth and proliferation, cellular metabolism, and angiogenesis. Mutations in TSC1 or TSC2 result in constitutive mTOR activation that drives the pathogenesis of TSC. Currently there are no approved systemic therapies to treat the underlying cause of TSC (ie, unregulated mTOR activity). Methods: Recently, an open-label, phase II trial (NCT00411619) of everolimus, an orally bioavailable, selective mTOR inhibitor, demonstrated a significant reduction in SEGA volume and a decreased frequency of seizures. Based on these promising efficacy data, additional phase II studies have been launched or are being planned to explore the benefit of everolimus in patients with neurological manifestations of TSC (Table). In addition, the ongoing EXIST-1 trial (EXamining everolimus In a Study of TSC; NCT00789828), a randomized, prospective, double-blind, multicenter study, is the first placebo-controlled phase III study in patients with TSC. Results: Everolimus has demonstrated promising efficacy in a phase II trial of patients with TSC. Conclusions: Additional rationale supporting mTOR inhibition as a therapeutic target in patients with TSC and detailed study designs will be presented.