Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy

Sophie F Hill; Paymaan Jafar-Nejad; Frank Rigo; Miriam H Meisler

doi:10.3389/fnins.2023.1282201

Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy

Front Neurosci. 2023 Oct 13:17:1282201. doi: 10.3389/fnins.2023.1282201. eCollection 2023.

Authors

Sophie F Hill^{1

2}, Paymaan Jafar-Nejad³, Frank Rigo³, Miriam H Meisler^{1

2

4}

Affiliations

¹ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States.
² Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States.
³ Ionis Pharmaceuticals, Carlsbad, CA, United States.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, United States.

Abstract

Developmental and epileptic encephalopathies (DEEs) are severe seizure disorders with inadequate treatment options. Gain- or loss-of-function mutations of neuronal ion channel genes, including potassium channels and voltage-gated sodium channels, are common causes of DEE. We previously demonstrated that reduced expression of the sodium channel gene Scn8a is therapeutic in mouse models of sodium and potassium channel mutations. In the current study, we tested whether reducing expression of the potassium channel gene Kcnt1 would be therapeutic in mice with mutation of the sodium channel genes Scn1a or Scn8a. A Kcnt1 antisense oligonucleotide (ASO) prolonged survival of both Scn1a and Scn8a mutant mice, suggesting a modulatory effect for KCNT1 on the balance between excitation and inhibition. The cation channel blocker quinidine was not effective in prolonging survival of the Scn8a mutant. Our results implicate KCNT1 as a therapeutic target for treatment of SCN1A and SCN8A epilepsy.

Keywords: ASO; Kcnt1; Scn1a; Scn8a; epilepsy; potassium channel; sodium channel.

Grants and funding

R01 NS034509/NS/NINDS NIH HHS/United States