Abstracts

Rationale: Dravet Syndrome is characterized by reduced expression of Na_V1.1 in inhibitory neurons that leads to hyperexcitability, resulting in epilepsy and multiple developmental co-morbidities (cognitive and motor deficits). The non-seizure symptoms of the disorder emerge early in life and worsen over time, significantly impacting the overall disease burden. Therefore, there is a pressing need for therapeutic interventions. To address this unmet medical need we are developing Nav1.1 isoform-selective small molecules.

Quantitative Electrocorticography (qECoG) can be used to evaluate background activity, to assess CNS target engagement and to determine pharmacokinetic and pharmacodynamic (PK/PD) properties of compounds. Using qECoG, we tested if background brain activity is different in juvenile DS mice compared to their wild-type (WT) littermates. Next, we assessed whether acute oral administration of a small set of Xenon-developed Nav1.1 isoform-selective small molecules (“XPC compounds”) could alter DS mice brain rhythms and modify the power of background activity in the WT.


Methods: Juvenile DS mice and WT littermates were implanted with cortical electrodes and a ground electrode between postnatal day (P) 35-40. After a recovery period of a week, video-ECoG were performed in freely moving mice. To measure baseline phenotype DS and WT mice were recorded for a period of 2 hours. To determine the effects of the XPC compounds on brain rhythms, DS and WT mice were first orally dosed with vehicle, and ECoG recordings were performed for 2 hours, then the XPC compounds were administered and the video-ECoG recordings were carried out for another 2 hours. Power spectral analysis was performed at different time-points.


Results: Differences in brain background activity between DS and WT mice were detected in delta, theta and alpha frequency bands of the power spectrum. Acute oral administration of the XPC compounds in DS mice modulated the spectral power mainly by decreasing spectral density for delta, theta and alpha frequency bands. We found that the XPC compounds attenuated the DS mice brain rhythms towards the WT spectra. Spectral analysis from WT mice dosed with the XPC compounds revealed reductions in power spectral density for delta, theta and alpha and increased power for gamma frequency bands.


Conclusions: In conclusion, for this model: 1. Background brain activity is different in DS mice compared to WT littermates during the stabilization period; 2. the XPC compounds can attenuate the brain rhythms that were altered in DS mice. 3. the XPC compounds produce detectable changes in power spectra in WT mice. Taken together, the acute effects of the XPC compounds on ECoG spectral properties suggest that Nav1.1 potentiation could normalize the power spectrum phenotype of Dravet mice and that qECoG may offer a potential readout of target engagement in clinical trials.


Funding: Xenon Pharmaceuticals