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(Abst. 3.051), 2019

Small Molecule Potentiators of NaV1.1 Increase Action Potential Firing in Fast Spiking Cortical Inhibitory Interneurons from a Mouse Model of Dravet Syndrome
Authors: Alison J. Cutts, Xenon Pharmaceuticals Inc; Aaron D. Williams, Xenon Pharmaceuticals Inc.; Maegan Soriano, Xenon Pharmaceuticals Inc.; Richard Dean, Xenon Pharmaceuticals Inc.; Verner Lofstrand, Xenon Pharmaceuticals Inc.; Charles J. Cohen, Xenon Pharmaceuticals Inc.; Steven Wesolowski, Xenon Pharmaceuticals Inc.; James R. Empfield, Xenon Pharmaceuticals Inc.; James P. Johnson Jr., Xenon Pharmaceuticals Inc.; Samuel J. Goodchild, Xenon Pharmaceuticals Inc.
Content: Rationale: Loss-of-function variants of SCN1A cause Dravet Syndrome (SMEI or EIEE6) and generalized epilepsy with febrile seizures plus (GEFS+), by decreasing NaV1.1 expression or conductance in inhibitory interneurons. The resulting hypo-excitability of interneurons reduces inhibitory input on excitatory neurons and leads to epilepsy and developmental delays. A precision medicine therapy for Dravet Syndrome should restore NaV1.1 activity specifically without impacting other neuronal proteins or conductances. We are pursuing brain penetrant small molecule enhancers of NaV1.1 currents to allow oral dosing and titration of the NaV1.1 current levels. We hope that such activators can directly address the underlying cause of Dravet Syndrome with the potential to provide a safe and effective pharmacotherapy.  Methods: We identified small molecule enhancers that selectively target NaV1.1, while sparing other voltage gated sodium channels. Patch clamp electrophysiology was used to examine the potency, and selectivity of Compound A. Compound A was evaluated in brain slices from SCN1A heterozygous null mice to assess the potential for enhancing interneuron excitability.  Results: Compound A is a potent enhancer of NaV1.1 and acts to impair inactivation of the channel. Compound A is selective and is a poor modulator of NaV1.2, NaV1.6 and NaV1.5. In brain slices from SCN1A+/- mice, Compound A increased the firing rate of inhibitory interneurons. Compound A treatment improved interneuron excitability, increasing maximum firing rate and or preventing collapse of firing at high stimulus input.  Conclusions: Selectively potentiating NaV1.1, the dominant sodium channel isoform expressed in inhibitory interneurons, restores the capability of those neurons to fire action potentials at high frequency. A small molecule pharmaceutical with this profile should enable reversal of the fundamental defect in Dravet Syndrome and may have utility in other neurologic indications where interneuron excitability is impaired. This profile provides a new, mechanistically differentiated, class of voltage-gated sodium channel potentiators with the potential to provide an improved therapeutic profile for Dravet Syndrome patients.  Funding: No funding