Focal cortical dysplasia type II (FCDII) and tuberous sclerosis complex (TSC) are two rare neurodevelopmental disorders each occurring in 1/6000 individuals. In both disorders, mutations affect genes involved in the AKT/mTOR signaling pathway and individuals display focal cortical malformations (FCM) that lead to epilepsy. In TSC, approximately 85% of the patients will have seizures, and nearly two-thirds of these patients will be refractory to treatment and will experience seizures for their life, leading to a spectrum of neurocognitive and psychological disabilities. It is anticipated that similar statistics are represented in FCDII patients. Two treatment options are available for TSC and FCDII patients. One is surgical resection for eligible patients. But only about 50% of the patients will effectively manage their seizures. The second one is treatment with the mTOR blocker, everolimus (Novartis), which (at the highest dose tested) reduced seizures by 40% in 40% of the patients and has grade >3-4 adverse events in 38% of the patients. There is thus a serious need to improve epilepsy treatment in TSC and FCDII patients. Recent work from our lab identified increased activity of the MAPK pathway in TSC and FCDII conditions leading to increased filamin A (FLNA) levels. Preliminary proof-of-concept data suggest that treatment with a small molecule modulator of FLNA function, PTI-125, significantly decreased seizure frequency in our mouse model of TSC and FCDII. PTI-125 binds to FLNA with high-affinity, rapidly enters the CNS of adult mice, and is approximately 90% orally bioavailable . We thus propose studies to optimize PTI-125 dosage and treatment paradigms for in vivo efficacy studies on epilepsy in TSC and FCDII. Our proposed drug therapy is fundamentally different from present treatment in TSC and FCDII considering that FLNA has never been considered as a potential therapeutic target in these disorders and is not downstream of mTOR signaling. In addition, we have developed a murine model of FCM-associated epilepsy that fully recapitulates the human TSC and FCDII disorder. We are thus in a unique position to test the proposed drug. PTI-125 has been obtained through a material transfer agreement with Pain Therapeutics, Inc. PTI-125 is in clinical development for Alzheimer?s disease and has completed the IND-enabling studies. Pain Therapeutics has thus already performed pharmacokinetics studies. The phase 61 proposes studies to inform design and refinement of the in vivo efficacy procedures. The R33 phase proposes in vivo efficacy studies of PTI-125 on seizures. .
This proposal aims at testing whether PTI-125, a small molecule modulator of filamin A function, can prevent epilepsy or significantly decrease seizure activity in a mouse model of tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII). TSC and FCDII are two rare neurodevelopmental disorders each occurring in 1/6000 individuals and associated with drug-resistant epilepsy in about 80% of the patients.