Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a complex genetic disorder characterized by benign tumors in many parts of the body including the brain, skin, kidneys and other organs. TSC is a type of cortical dysplasia that is associated with developmental disabilities. About a third of the cases are genetically inherited from an affected parent who carries mutations in the TSC1 or TSC2 gene but the remaining two-thirds are due to new mutations that arose spontaneously.

Research conducted in the Gordon and Mary Cain Foundation Laboratories for Pediatric Neurology led to the following important milestones in finding a treatment for TSC-related seizures -

  • Short-term rapamycin treatment strongly suppressed the severity and duration of seizures as well as neuronal overgrowth in a mouse model of cortical dysplasia. Read more
  • Inhibiting the mTOR signaling pathway with a single course of rapamycin suppressed epilepsy for several weeks before seizures recurred again. However, additional intermittent treatments with rapamycin prevented this recurrence. This treatment also prolonged the survival of mice and did not affect its growth. Read more
  • The mTOR and extracellular regulated kinase (ERK) signaling pathways are upregulated in Tuberous Sclerosis and focal cortical dysplasia (FCD) patients. Read more
  • In 2010, extensive preclinical cellular and animal studies by Cain lab researchers culminated in the identification of a rapamycin analog, everolimus, as a potential therapy against severe epilepsy due to brain malformations in Tuberous Sclerosis Complex. In a small FDA-approved clinical trial with 20 patients was conducted at the Texas Children’s and Cincinnati Children’s Hospitals. The results showed that most of the severely epileptic children treated with everolimus had significantly fewer seizures.  Read more
  • Encouraged by those positive results, much larger international clinical trial (EXIST -3) of 366 patients was undertaken. About 15% reduction in seizure frequency was observed in patients who were administered with low-exposure everolimus and 25% reduction was observed in those who were administered high-exposure everolimus. This established that adjunctive everolimus therapy can significantly reduce seizures in TSC patients, is well-tolerated and safe. Read More
  • Recently, everolimus was approved by both the European Union and FDA as a treatment for TSC-associated seizures. Read more