Selective Potentiation of NaV1.1 Channels by Small Molecule XPC-837 in Dravet Mice Suppresses Spontaneous Seizures, Prevents SUDEP, and Increases Long Term Potentiation
Alison Cutts1, Samuel Goodchild1, Kristen Burford1, Celine Dube1, Samrat Thouta1, Arjun Mahadevan1, Matthew Waldbrook1, Maegan Soriano1, Maja Filipovic1, Vishaal Rajani1, Emily Hurley1, Verner Lofstrand1, Helen Clement1, Davie Kim1, Steve Wesolowski1, James Empfield1, JP Johnson1
1Xenon Pharmaceuticals
Objective:
To develop a novel, mechanistically differentiated, orally available compound with the potential to provide an improved therapeutic profile for the treatment of seizure and non-seizure symptoms of Dravet Syndrome (DS).
Background:
Loss-of-function variants of SCN1A cause DS by decreasing NaV1.1 expression in inhibitory interneurons. The resulting hypo-excitability of interneurons reduces inhibitory input on excitatory neurons and leads to epilepsy and developmental delays. We are developing orally available NaV1.1 potentiators that could provide a potentially disease modifying precision therapy for DS.
Design/Methods:
Automated patch clamp electrophysiology was used to evaluate the potency and selectivity of compounds. XPC-837 was also evaluated in brain slices from Scn1a heterozygous null mice (Scn1a+/-) to assess the effects on interneuron excitability, synaptic inhibitory and excitatory balance, and Long Term Potentiation (LTP). Repeat dose efficacy in was assessed Scn1a+/- mice by spontaneous seizure frequency and mortality.
Results:
XPC-837 exhibited robust enhancement of NaV1.1, demonstrating more than a 100-fold preference over NaV1.2, 1.6, and 1.5 variants. In brain slices obtained from Scn1a+/- mice, XPC-837 increased the firing activity of fast-spiking cortical PV+ interneurons and rebalanced the spontaneous excitatory and inhibitory synaptic input to pyramidal neurons. In vivo experiments further show that XPC-837 effectively mitigates 6Hz electrically induced seizures in Scn1a+/- mice and improves their motor performance deficits. Feeding XPC-837 medicated chow for 14 days demonstrated that XPC-837 suppresses spontaneous seizures, prevents SUDEP, and increases LTP in Scn1a+/- mice.
Conclusions:
XPC-837 is a highly NaV1.1 selective small molecule potentiator that increases Scn1a+/- interneuron excitability and normalizes excitation/inhibition imbalance in Scn1a+/- mouse neurons. In vivo, XPC-837 suppresses induced seizures and improves motor performance, suppresses spontaneous seizures, prevents SUDEP and increases LTP. XPC-837 represents a novel, mechanistically differentiated, orally available compound with the potential to provide an improved therapeutic profile for the treatment seizure and non-seizure symptoms of DS.
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