Translational Studies in Tuberous Sclerosis

Background: Accumulating evidence suggests that tuberous sclerosis complex (TSC) patients have non-tuber abnormalities that contribute to the development of the neurological and behavioral phenotype. Using mouse models of TSC, work from our lab with our collaborators has started to shed light on the cellular and neural circuit abnormalities underlying the neurobehavioral problems. We have shown that TSC1/2 proteins regulate axon specification, guidance, myelination and regeneration, suggesting that TSC-deficiency will lead to circuit-level abnormalities and contribute to autism-related phenotypes in TSC mouse models and patients.

Objectives: We set out to test the safety and efficacy of mTOR inhibitors first on mouse models.

Methods: We treated neuronal-specific or cerebellar Purkinje cell-specific Tsc1 knockout mouse models, which displays autistic-like features, with rapamycin starting at the time of Tsc1 deletion. We also initiated a placebo-controlled double-blind Phase II trial of everolimus, a rapamycin homolog, in TSC patients with neurocognition as the primary endpoint.

Results: mTOR inhibitor treatment trial starting early in life can prevent autistic-like behaviors in the Purkinje cell-specific knockout.

Conclusions: Taken together, these preclinical studies have lead to collaborative biomarker and treatment trials that are currently ongoing. Updates will be provided from the results of the ongoing biomarker and treatment trials with patients with TSC.