Selective Potentiation of NaV1.1 Channels in Dravet Mice Suppresses Spontaneous Seziures, Prevents SUDEP and Increases Long Term Potentiation.
Abstract number :
3.181
Submission category :
2. Translational Research / 2D. Models
Year :
2025
Submission ID :
623
Source :
www.aesnet.org
Presentation date :
12/8/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Samuel Goodchild, PhD – Xenon Pharmaceuticals
Kristen Burford, PhD – Xenon Pharmaceuticals
Celine Dube, Ph – Xenon Pharmaceuticals
Samrat Thouta, Ph – Xenon Pharmaceuticals
Arjun Mahadevan, PhD – Xenon Pharmaceuticals
Matt Waldbrook, BS – Xenon Pharmaceuticals
Alison Cutts, PhD – Xenon Pharmaceuticals
Maegan Soriano, BS – Xenon Pharmaceuticals
Maja Filipovic, BS – Xenon Pharmaceuticals
Vishaal Rajani, PhD – Xenon Pharmaceuticals
Emily Hurley, PhD – Xenon Pharmaceuticals
Verner Lofstrand, PhD – Xenon Pharmaceuticals
Helen Clement, PhD – Xenon Pharmaceuticals
Davie Kim, BS – Xenon Pharmaceuticals
Steven Wesolowski, PhD – Xenon Pharmaceuticals
Jim Empfield, PhD – Xenon Pharmaceuticals
JP Johnson, PhD – Xenon Pharmaceuticals
Rationale: Dravet Syndrome is a condition marked by diminished expression of NaV1.1 in inhibitory neurons, resulting in heightened network excitability due to impaired inhibitory activity. Impairment of inhibitory activity can lead to epilepsy and delays in cognitive and motor function. To meet this urgent clinical demand, we have focused on developing a precision medicine therapy that enhances NaV1.1 activity exclusively, without interfering with other neuronal functions or proteins. We aim to develop potent, isoform-selective small molecules, that are suitable for oral administration and are capable of crossing the blood-brain barrier to amplify NaV1.1 channel currents. By directly potentiating the remaining NaV1.1 channels in Dravet Syndrome, these compounds represent a promising avenue for disease-modifying pharmacotherapy.
Methods: Automated patch clamp electrophysiology was used to evaluate the potency and selectivity of compounds. Compounds were also evaluated in brain slices from Scn1a heterozygous null mice (Scn1a+/-) to assess the effects on interneuron excitability and inhibitory/excitatory balance. Acute efficacy was assessed after oral dosing in Scn1a+/- mice in a rotorod motor performance assay Scn1a+/- mice fed medicated chow from P21-P35 were evaluated for suppression of spontaneous seizures, protection from SUDEP, changes in hippocampal long-term potentiation (LTP), and changes to dendritic spine morphology.
Results: Compound XPC-A exhibited robust enhancement of NaV1.1 channels, demonstrating a more than 100-fold preference over NaV1.2, 1.6, and 1.5 variants. Through biophysical analysis, we established that XPC-A selectively disrupted the inactivated state of NaV1.1 channels. In brain slices obtained from Scn1a+/- mice, XPC-A increased the firing activity of fast-spiking cortical PV+ interneurons and reinstated the equilibrium between spontaneous excitatory and inhibitory synaptic input to pyramidal neurons. Acute in vivo experiments further show that XPC-A improved their motor performance deficits as evaluated by the rotarod assay. In addition, chronic dosing of XPC-A in chow suppressed spontaneous seizures, protected animals from SUDEP, increased LTP and normalized dendritic spine morphology.
Conclusions: Potent and selective enhancers of NaV1.1 can augment the excitability of fast-spiking inhibitory neurons and rebalance excitation/inhibition balance in brain slices from Scn1a+/- mice. Notably, XPC-A enhanced motor performance in Scn1a+/- mice during the rotarod test, supporting the potential to mitigate the non-seizure symptoms linked with Dravet Syndrome. Chronic dosing over 14 days with XPC-A in chow suppressed spontaneous seizures, prevented SUDEP and increased LTP, suggesting the potential for disease modifying effects. From these studies, XPC-A emerges as a pioneering mechanism for enhancing voltage-gated sodium channels, offering promise as a therapeutic approach that could modify the course of Dravet Syndrome.
Funding: This work was funded by Xenon Pharmaceuticals
Translational Research