Focal Cortical Dysplasia (FCD) is a rare neurological disorder representing up to 39% of pediatric epilepsy surgery cases. These conditions manifest as drug-resistant seizures with developmental delays in early childhood. Over 80% of FCD patients do not respond to conventional antiepileptic drugs, making invasive neurosurgical resection the primary treatment option.
Recent research has advanced understanding of FCD pathophysiology, demonstrating that most cases result from brain somatic mutations in mTOR pathway genes (MTOR, PIK3CA, AKT3, DEPDC5). These mutations create a mosaic pattern where abnormal cytomegalic cells display mTOR hyperactivity and generate epileptogenic activity. Current approaches targeting the mTOR pathway systemically have shown limited efficacy, as demonstrated by clinical trials with rapamycin/everolimus that failed to significantly reduce seizures.
Building on findings from the EpiTOR ERC Consolidator Grant, our research identified cellular senescence signatures specifically present in abnormal FCD cells. FCDII tissues consistently display senescence hallmarks, including p53/p16 expression and senescence-associated β-galactosidase activity, exclusively in pathogenic mutated cells responsible for seizure generation, unlike normal brain tissue or other epilepsy types.
This discovery enables a precision medicine approach using senolytic drugs—FDA-approved agents that selectively eliminate senescent cells through targeted apoptosis. Our preliminary data shows that oral administration of dasatinib plus quercetin (DQ) effectively clears abnormal senescent cells and reduces seizure frequency in preclinical mouse models, offering a "hit-and-run" therapeutic strategy that may provide sustained seizure control without chronic medication.
Overall Objectives: EpiSen aims to translate this scientific discovery into clinically viable precision therapy for childhood refractory epilepsies through three objectives: (1) Preclinical validation of senolytic therapy in two distinct FCD mouse models, demonstrating senescent cell clearance and sustained seizure reduction; (2) Intellectual property protection, Orphan Drug Designation pursuit, and strategic pharmaceutical partnerships; (3) Design Phase 2 clinical trial testing DQ combination in children with drug-resistant FCD-related epilepsy.
Expected Impact: EpiSen could significantly advance childhood epilepsy treatment. Unlike symptomatic treatments, this approach targets underlying pathophysiology through selective elimination of epileptogenic cells, potentially offering sustained seizure control, precision targeting that preserves normal brain tissue, broad applicability regardless of specific mutations, reduced need for surgical intervention, and improved quality of life. This therapeutic strategy may extend to other "mTORopathies" including tuberous sclerosis complex, contributing to precision medicine development in rare neurological disorders. The approach addresses an important unmet medical need and could establish new treatment paradigms for rapid translation of mechanistic discoveries into clinical therapies.
