Treating epilepsy in tuberous sclerosis with everolimus: getting closer.

Commentary Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ system, especially the brain, retina, heart, skin, kidney, lung, and liver. Neurological manifestations are responsible for most disability , and include cognitive impairment and subependymal giant cell astrocytomas (SEGAs), but epilepsy is the most common problem, occurring in about 90 percent of individuals with TSC. The epilepsy typically begins early in life and is often intractable. Most TSC cases arise from new inactivating mutations in the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) tumor suppressing genes. The molecular mechanism of TSC is hyperactivity of the " mammalian target of rapamycin " (mTOR) pathway, which is felt to be responsible for both the hamartomas and epilepsy (1). mTOR is a protein kinase that regulates cell growth, proliferation , and survival, as well as expression of neurotransmitter receptors, synaptic plasticity, and axonal and dendritic morphology. Hamartin and tuberin form a complex that activates a GTPase (guansosine triphosphate hydrolase) that inactivates the RHEB (RAS protein homologue enriched in brain)-signaling protein, leading to inhibition of the mTOR pathway; mutations of TSC1 or TSC2 therefore release inhibition of this pathway. Rapamycin, initially developed as an antifungal agent, was the first agent determined to inhibit the mTOR system (2). It was shown to cause regression of SEGAs in humans with TSC (3). In addition, early treatment with rapamycin was shown to prevent premature death and development of epilepsy in experimental models of TSC such as the TSC1 GFAP conditional knockout mouse (4), leading to investigation of mTOR inhibi-tors as therapy for human TSC. Most clinical investigations have been done with evero-limus, a rapamycin analog that was originally FDA approved for immunosuppression to prevent organ rejection following renal and cardiac transplantation, and as treatment for meta-static renal cell carcinoma. Marked regression of SEGAs within 3 months of treatment was demonstrated in an open study (5), and then confirmed in a large, international, multicenter, double-blind, placebo-controlled phase III trial (6). The FDA and the European Medicines Agency now approve everolimus for treatment of SEGAs that cannot be cured by neurosurgery. The patients in the open trial have now been followed for approximately 3 years with an observed sustained response (7). OBJECTIVE: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is a mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the …