Research ArticleEpilepsy

Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations

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Science Translational Medicine  19 Feb 2020:
Vol. 12, Issue 531, eaay0289
DOI: 10.1126/scitranslmed.aay0289

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Targeting actin-binding protein in cortical malformations

Mutations in the mammalian target of rapamycin (mTOR) pathway cause focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). These disorders are associated with pharmacoresistant epilepsy. Often, the only available treatment is the resection of the epileptic focus, an invasive intervention with severe side effects. Now, Zhang et al. used human brain tissue from resections and mouse models to identify pharmacological targets. They found that filamin A (FLNA) expression is increased in tissue from patients with FCD. Inhibiting FLNA in a mouse model of FCD and TSC after seizure onset reduced seizure frequency and neuronal abnormalities. The results suggest that inhibiting FLNA might be therapeutic in patients with FCD and TSC.


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. Here, 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. 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. 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.

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