Abstract Details

Title Selective Potentiation of NaV1.1 Channels by Small Molecule XPC-837 in Dravet Mice Suppresses Spontaneous Seizures, Prevents SUDEP, and Increases Long Term Potentiation

Topic Child Neurology and Developmental Neurology

Presentation(s) S19 - Emerging Therapies in Child Neurology (4:06 PM-4:18 PM)

Poster/Presentation
Number 004

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 Na_V1.1 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 Na_V1.1 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 Na_V1.1, demonstrating more than a 100-fold preference over Na_V1.2, 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 Na_V1.1 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.

Authors/Disclosures
Alison Cutts PRESENTER	Alison Cutts has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Alison Cutts has stock in Xenon Pharmaceuticals. Alison Cutts has received intellectual property interests from a discovery or technology relating to health care.
Samuel J. Goodchild, PhD	Dr. Goodchild has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Goodchild has stock in Xenon Pharmaceuticals.
Kristen Burford	Dr. Burford has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Burford has stock in Xenon Pharmaceuticals. Dr. Burford has received intellectual property interests from a discovery or technology relating to health care.
Celine M. Dube, PhD	Dr. Dube has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Dube has stock in Xenon Pharmaceuticals.
samrat thouta, PhD	Dr. thouta has received personal compensation for serving as an employee of Xenon Pharamceuticals. Dr. thouta has stock in Xenon Pharmaceuticals.
Arjun Mahadevan, MSc	Mr. Mahadevan has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc. Mr. Mahadevan has stock in Xenon Pharmaceuticals Inc.
Matthew Waldbrook	Mr. Waldbrook has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Mr. Waldbrook has stock in Xenon Pharmaceuticals.
Maegan Soriano, BSc	Ms. Soriano has received personal compensation for serving as an employee of Xenon Pharmaceuticals . Ms. Soriano has stock in Xenon Pharmaceuticals .
Maja Filipovic, BSc	Ms. Filipovic has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Ms. Filipovic has stock in Xenon Pharmaceuticals.
Vishaal Rajani, PhD	Dr. Rajani has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc.. Dr. Rajani has stock in Xenon Pharmaceuticals Inc..
Emily Hurley	Ms. Hurley has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc..
Verner A. Lofstrand, PhD	Mr. Lofstrand has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Mr. Lofstrand has stock in Xenon Pharmaceuticals. Mr. Lofstrand has received intellectual property interests from a discovery or technology relating to health care.
Harrison Clement, MS	Mr. Clement has nothing to disclose.
Jung Yun Kim	Mr. Kim has received personal compensation for serving as an employee of Xenon Pharmaceuticals Inc.. Mr. Kim has stock in Xenon Pharmaceuticals. Mr. Kim has received publishing royalties from a publication relating to health care.
Steven Wesolowski, PhD	Dr. Wesolowski has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Wesolowski has stock in Xenon Pharmaceuticals. Dr. Wesolowski has received intellectual property interests from a discovery or technology relating to health care.
James Empfield, PhD	Dr. Empfield has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Empfield has stock in Xenon Pharmaceuticals.
J.P Johnson Jr, PhD	Dr. Johnson Jr has received personal compensation for serving as an employee of Xenon Pharmaceuticals. Dr. Johnson Jr has stock in Xenon Pharmaceuticals. Dr. Johnson Jr has received intellectual property interests from a discovery or technology relating to health care.

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