Authors :
Presenting Author: Jennifer Koehler, BA – University of Wisconsin-Madison
Olivia Hoffman, PhD – University of Wisconsin-Madison
Jose Ezekiel Espina, MS – University of Wisconsin-Madison
Emily Gohar, BS – University of Wisconsin-Madison
Emanuel Coleman, BA – Tufts University School of Medicine
Barry Schoenike, MS – University of Wisconsin-Madison
Raymond Dingledine, PhD – Emory University School of Medicine
Jamie Maguire, PhD – Tufts University School of Medicine
Avtar Roopra, PhD – University of Wisconsin-Madison
Rationale:
Despite the development of 25 antiepileptic medications (AEMs) in the last 25 years 1/3 of patient’s seizures are resistant to medication. Furthermore, many anti-epileptic medications effective for seizure suppression exacerbate comorbidities in patients with epilepsy-related cognitive decline. Patients with drug resistant epilepsy report that the adverse effects of their medications along with their comorbidities can have a greater negative impact on their quality of life then their seizures. Previous data identified STAT3 as a driver of upregulated genes across cell types in chronic rodent epilepsy and humans with drug-resistant temporal lobe epilepsy. We have successfully repurposed the FDA approved drug CP690550 to enduringly suppress seizures and rescue cognitive decline in chronically epileptic mice. We show that CP690550 also suppresses seizures and rescues cognition in a drug-resistant mouse model of epilepsy.
Methods:
We developed a mouse model of drug-resistant epilepsy by screening epileptic mice with the commonly prescribed anti-epileptic medication valproate (150 mg/kg twice daily) for two weeks followed by two weeks of treatment with CP690550 (15 mg/kg). We employed behavioral seizure monitoring for a reduction in seizure frequency greater than or equal to 50% to separate valproate responders from drug-resistant mice and test CP690550’s ability to suppress seizures after a known AEM failed. We utilized spontaneous and forced alternation tests to monitor deficits in working and short-term memory and assess CP690550’s ability to rescue decline in drug resistant animals.
Results:
Building on our previous finding that treating chronically epileptic mice with CP690550 enduringly suppresses seizures, we find that treatment CP690550 significantly suppresses seizures in mice that fail to respond to valproate treatment. Furthermore, while most patients that fail to respond to their first AEM only have a 10-15% response rate on their second AEM, 60% of mice treated with CP690550 met the clinical threshold for seizure reduction. We also show that CP690550 rescues short term memory back to naïve levels even after valproate treatment has failed to improve memory.
Conclusions:
We show that the reignition of the JAK/STAT signaling pathway in chronic epilepsy opens a second, potent therapeutic window targetable using the FDA approved drug, CP690550 which effectively suppresses seizures and rescues cognitive decline in a drug-resistant model of epilepsy.
Funding:
Supported by CURE (AR), Lily’s Fund (AR), NIH grant T32 GM14103 (JK), 1R01NS108756 (AR, RD) and R01NS105628, R01NS102937, and R21NS120868 (JM).