Research Associate Scientist Yale University New Haven
This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Methods: We show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Then we test whether targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 can reduce seizures in TSC or FCDII mice model. Results: Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. Conclusions: These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes. Funding: Please list any funding that was received in support of this abstract.: This work was supported by NIH R01 NS093704 (A.B.), R61 NS111074 (A.B.), Swebilius Foundation (A.B.), National Natural Science Foundation of China 81671123 (L.Z.), and American Epilepsy Society postdoctoral fellowship (L.H.N.).