Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

Science Translational Medicine  24 Apr 2013:
Vol. 5, Issue 182, pp. 182ra53
DOI: 10.1126/scitranslmed.3005271

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Preventing Seizures with Rapamycin

The discovery of new treatments for rare neurodevelopmental disorders associated with epilepsy and intellectual disability is often limited by small patient sample sizes that delay initiation of clinical trials. Mutations in the gene STRADA cause brain malformations, seizures, and failure to develop social language in children, with no known successful treatment. In a new study, Parker and colleagues now show that the protein STRADA modulates the mammalian target of rapamycin (mTOR) signaling pathway and that loss of STRADA results in unchecked mTOR activity. Depletion of STRADA in mouse neural progenitor cells resulted in loss of polarity, impaired migration, and inability to form layers in the cerebral cortex. Impaired migration was also identified in fibroblasts from patients lacking STRADA, and all of these effects were prevented with the mTOR inhibitor rapamycin, an immunosuppressant drug in clinical use. The authors then treated five children with rapamycin (sirolimus) beginning at 3 to 8 months of age, and abatement of seizures was observed in all of the children. Early treatment with mTOR pathway inhibitors may be beneficial for children with this neurodevelopmental disorder or with other conditions associated with enhanced mTOR signaling such as tuberous sclerosis complex and fragile X syndrome.