Brittany Spitznagel, PharmD

Malignant migrating partial seizures of infancy (MMPSI) is a rare, severe form of early-onset epileptic encephalopathy, characterized by focal seizures that arise from various regions of either brain hemisphere and can migrate between brain regions. The majority of these patients experience recurrent seizures before six months of age, ranging from 5 to 50 seizures per day. Due to the severity and number of seizures, affected individuals suffer profound developmental delays and intellectual impairment. Most notably, MMPSI patients have arrest or regression of motor skills obtained prior to the onset of seizure activity. The majority of MMPSI cases are considered pharmacoresistant, causing patients to progress in their disease and not survive past early childhood. Growing evidence suggests a genetic etiology for the development of MMPSI. To date, thirty-one de novo mutations affecting three functional domains of the potassium (K+) channel Slack have been reported in greater than 50% of patients with MMPSI, making it the most frequent known genetic signature associated with MMPSI. This project focuses on these Slack mutations, their link to epilepsy and attempting to correct this epileptiform behavior with pharmacologic tools. Slack is a member of the Slo family of K+ channels, encoded by the gene KCNT1. This channel family is a critical regulator of electrical activity in the nervous system. Slack channels are widely distributed throughout the central nervous system, where they contribute to the slow hyper-polarization of neurons following action potential firing. A large number of mutations have been reported in Slack. All mutations described have been shown to induce PhRMA Foundation | Annual Report 2019 49 a dominant gain-of-function by several mechanisms, including 3-12 fold increases in current amplitudes, a left shift in the current-voltage relationship or increasing the channel’s sensitivity to Na+ ions. This research has focused on the A934T mutation as it is associated with the most severe human MMSPI phenotype and was used to generate a transgenic mouse. The lack of potent and selective pharmacological tools has inhibited researchers from understanding the role Slack plays in childhood epilepsies and investigating it as target for therapeutic intervention. The development of such tools is well underway, with the first selective Slack modulator identified through a high-throughput screening efforts. Additionally, this project has generated an MMPSI-associated mutant Slack mouse model to explore changes in EEG activity, anxietyrelated behaviors, motor and sensorimotor function. Together these pharmacologic and genetic approaches have allowed for significant advances in the fields of Slack and MMPSI research.