Positive Allosteric Modulation of kv3.1 Potassium Channels Protects Against Early Mortality and Seizures in a Mouse Dravet Syndrome Model
Abstract number :
1.243
Submission category :
2. Translational Research / 2E. Other
Year :
2024
Submission ID :
1080
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Yongho Choe, – Boston Children's Hospital
Mustafa Hameed, MD – Boston Children's Hospital
Sheryl Anne Vermudez, PhD – Boston Children's Hospital
Alexander Rotenberg, MD PhD – Boston Children's Hospital - Harvard Medical School
Rationale:
Dravet syndrome (DS) is caused by pathogenic variants in the SCN1A gene, leading Nav1.1 voltage-gated sodium channel haploinsufficiency. Reduced parvalbumin-positive interneuron (PVI) firing resultant from Nav1.1 deficiency is a major DS pathophysiology. The Kv3.1 voltage-gated potassium channel is preferentially expressed in PVIs, is critical for their fast-spiking properties, and its expression is also depressed in a mouse DS (Scn1a+/-) model. Patients with DS often have drug-resistant seizures, severe developmental delay, and an increased risk for sudden unexpected death in epilepsy (SUDEP). Since conventional anti-seizure drugs are largely ineffective in DS, a novel anti-seizure DS therapeutic target is thus highly desirable. Given Kv3.1’s role in PVI function, we tested whether Kv3.1 positive allosteric modulation (PAM) suppresses seizures in a DS mouse model.
Methods:
Juvenile P17-19 Scn1a+/- mice (n=25) were injected intraperitoneally (IP) with vehicle (VEH) (n=15) or AUT1 (a Kv3.1 PAM; n=10) 30 min prior to induction of hyperthermia-induced (febrile) seizures (FS) using an infrared lamp. A second cohort of juvenile Scn1a+/- mice (n=18) were administered either AUT1 (n=12) or VEH (n=6) twice daily for 2 weeks starting at P17. Lastly, one cohort of adult Scn1a+/- mice (n=42) were implanted with wireless EEG transmitters and underwent baseline video-EEG monitoring for generalized tonic-clonic seizures (GTCS) for 7 days. Mice with GTCS (n=18) were randomly assigned to receive daily IP (1) VEH, (2) AUT1, or (3) AUT63 (a second Kv3.1 PAM) while undergoing an additional week of video-EEG monitoring. Where appropriate, data were normalized to baseline. Statistical analyses were performed on raw or normalized data.
Results:
AUT1 treatment delayed FS onset in juvenile Scn1a+/- mice (log-rank test; p=0.017) and significantly increased mean FS temperature threshold (increase from baseline temperature; VEH: +4.5 ± 0.8 ºC; AUT1: +5.3 ± 1.2 ºC, unpaired t-test; p=0.046). Only 10% of AUT1-treated mice developed FS at the VEH group median FS threshold of +4.3C from baseline (Fisher’s exact; p=0.041). Long-term AUT1 treatment also reduced the mortality in juvenile Scn1a+/- mice (log-rank; p=0.011). 100% of VEH treated controls died by P32 compared to 42% of AUT1 treated mice (Fisher’s exact test; p=0.038). This Kv3.1 mediated anti-epileptic effect was conserved in adult seizing Scn1a+/- mice where spontaneous seizure frequency was reduced by two Kv3.1 PAMs (one-way ANOVA; p = 0.0127), with both AUT1 (53.5 ± 31.7 % baseline; Tukey’s; p = 0.026) and AUT63 (46.8 ± 25.9 %baseline; Tukey’s; p = 0.022) significantly reducing seizure frequency compared to VEH treatment (255.5 ± 202.8 %baseline).
Conclusions:
Acute Kv3.1 potentiation may protect against early mortality and both febrile and spontaneous seizures in DS. These results provide a basis for continued work on developing novel DS therapies based on rational drug design targeting Kv3.1 channel biology.
Funding: NIMH 5T32MH112510, Autifony Therapeutics.
Translational Research