Profound seizure suppression and disease modification by targeting JAK1, a key driver of a pro-epileptogenic gene network

ABSTRACT Epilepsy is the 4th most prevalent neurological disorder with over 50 million cases worldwide 1,2 . While a number of drugs exist to suppress seizures, approximately 1/3 of patients remain drug resistant, and no current treatments are disease modifying 3 . Using network and systems-based approaches, we find that the histone methylase EZH2 suppresses epileptogenesis and slows disease progression, via repression of JAK1 and STAT3 signaling in hippocampal neurons. Pharmacological inhibition of JAK1 with the orally available, FDA-approved drug CP690550 (Tofacitinib) 4,5 virtually eliminates behavioral and electrographic seizures after the onset of epilepsy in a preclinical rodent model of acquired epilepsy. Overall, identification of an endogenous protective response to status epilepticus in the form of EZH2 induction has highlighted a critical role for the JAK1 kinase and STAT3 in both the initiation and propagation of epilepsy across preclinical rodent models and human disease. Targeting JAK1 with CP690550 has a profound therapeutic effect on spontaneous, recurrent seizures.