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

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.

Figure 1

Kcnt1 ASO reduces Kcnt1 transcript abundance. (A) The Kcnt1 ASO targets the proximal 3’UTR of the Kcnt1 transcript. (B) Expression of Kcnt1 in brain and spinal cord from P21 wildtype mice treated with Kcnt1 ASO on P2, measured by qRT-PCR (*** = p < 0.0001, Sidak’s multiple comparisons test).

Figure 2

Kcnt1 ASO prolongs survival of Scn8a mutant mice. Survival of Scn8a^cond/+,EIIa-Cre (W/+) mice treated with 15–45 μg Kcnt1 ASO at P2 compared with a cohort of contemporaneous control mice treated with control ASO [Control data was previously published in Lenk et al. (2020)]. Asterisks indicate significance of Mantel-Cox log-rank tests: * = p < 0.05, *** = p < 0.0001.

Figure 3

Quinidine does not prolong survival of Scn8a mutant mice. Survival of Scn8a^cond/+,EIIa-Cre (W/+) mice daily treated with 50 or 100 mg/kg quinidine compared to untreated mice. Grey shading indicates treatment period.

Figure 4

Kcnt1 ASO prolongs survival of Scn1a^+/− mice. Survival of Scn1a^+/− mice treated with 45 μg Kcnt1 ASO at P2 compared to untreated mice (p = 0.0513, Mantel-Cox log-rank test). Grey shading indicates the critical period in the development of Dravet Syndrome.