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

Abstract

A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…Treatment with the mTOR inhibitor rapamycin in both the mouse model and cell lines rescued the phenotype caused by loss of STRADA. These preclinical data led to a small open trial of rapamycin (sirolimus in clinical parlance) in five PS children for 8 months to 4 years, which showed prevention of seizures in these patients (Parker et al 2013). This was the first study to show epilepsy prevention with an mTOR inhibitor and suggested that early treatment could dramatically alter clinical seizure onset.…”

“…PS postmortem brain tissue contains enlarged dysmorphic neurons as well as heterotopic neurons within the subcortical white matter show numerous phospho-S6-and phospho-p70S6-kinase-labeled neurons, similar to FCDIIB and tubers. STRADA shRNA knockdown in vivo in fetal mouse brain induces mTORC1 activation, neuronal enlargement, laminar disorganization, and subcortical white matter heterotopias similar to human PS (Orlova et al 2010a ;Parker et al 2013). Furthermore, there are severe impairments in cell motility, directionality, and polarity in mouse neural progenitor cells lacking STRADA (Orlova et al 2010a;Parker et al 2013).…”

“…STRADA shRNA knockdown in vivo in fetal mouse brain induces mTORC1 activation, neuronal enlargement, laminar disorganization, and subcortical white matter heterotopias similar to human PS (Orlova et al 2010a ;Parker et al 2013). Furthermore, there are severe impairments in cell motility, directionality, and polarity in mouse neural progenitor cells lacking STRADA (Orlova et al 2010a;Parker et al 2013). Treatment with the mTOR inhibitor rapamycin in both the mouse model and cell lines rescued the phenotype caused by loss of STRADA.…”

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

“…Genes responsible for regulation of mTORC1 have been identified in epileptic patients with isolated focal cortical dysplasia IIb, 30,31 hemimegencephaly, 32 and syndromic epilepsies caused by DEPDEC5, 32,33 PTEN, 34 and STRADA. 35 Loss of mTORC1 regulation has been identified in animal models of acquired epilepsies, including temporal lobe epilepsy and posttraumatic epilepsy, which are responsive to sirolimus treatment. 36,37 Human patients with early-onset intractable epilepsy caused by STRADA mutation demonstrate marked reduction in seizure frequency when treated with sirolimus.…”

“…36,37 Human patients with early-onset intractable epilepsy caused by STRADA mutation demonstrate marked reduction in seizure frequency when treated with sirolimus. 35 Thus targeting the mTOR pathway with mTORC1 inhibitors such as everolimus may have application well beyond epilepsy associated solely with TSC.…”