Clinical Investigations in TSC

Background: Rare genetic diseases that affect behavior and cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of animal models, which can lead to development of hypotheses and treatments testable in human beings. Tuberous sclerosis complex (TSC) is an autosomal dominant disease that presents with autism, epilepsy, and intellectual disability. TSC can be diagnosed very early in life before autism symptoms arise. This provides a unique opportunity to study the pathogenesis underlying autistic symptoms in TSC and identifying signaling pathways that may be targeted for novel treatments.

Objectives: A series of knockout mouse models have been used to examine the role of Tsc1 and Tsc2 genes in neuronal development and function. These studies all indicate the mTORC1 inhibitors are effective in improving the neurological deficits in the animal models, including epilepsy and autism-like behaviors. Now, the challenge is to translate these funding to TSC patients.

Methods: As an initial step, we launched a Phase II clinical trial testing the efficacy of an mTOR inhibitor on improving neurocognition in children with TSC (NCT01289912). Children with TSC between the ages of 6 and 21 years were recruited to this study.

Results: One of the key issues that remain unanswered in the translation from preclinical to clinical trials is the selection of primary outcome measures. For this trial, the primary endpoint is neurocognition; secondary endpoints are autism, epilepsy and sleep disturbances. Inclusion criteria included an IQ cut off of 60 and higher so the subjects could complete the neurocognitive battery. 47 subjects were randomized; 32 patients were enrolled in the treatment group and 15 patients in the placebo groups. The two groups were comparable in terms of demographics and past medical history. Testing was performed at 0, 3 and 6 months. Analysis of the results is ongoing.

Conclusions: Single gene disorders with high penetrance of autism such as TSC provide powerful model systems to study the roles of individual molecules and associated signaling pathways in the genesis of autism, epilepsy, cognitive impairment and neuropsychiatric symptoms. Future trials need to incorporate translational biomarkers that can be employed in both animal models and patients. These diseases are leading to disease-modifying human therapies that may eventually translate to wider therapeutic strategies for autism.