Antisense oligonucleotide therapy for KCNT1 encephalopathy

Burbano, Lisseth; Li, Melody; Jancovski, Nikola; Jafar‐Nejad, Paymaan; Richards, Kay; Sedo, Alicia; Soriano, Armand; Rollo, Ben; Jia, Linghan; Piltz, Sandra; Adikusuma, Fatwa; Thomas, Paul Q.; Kopsidas, Helen; Rigo, Frank; Reid, C.; Maljevic, Snezana; Petrou, Steven

doi:10.1172/jci.insight.146090

Cited by 20 publications

(15 citation statements)

References 70 publications

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“…Not all SUDEP mice died and the age of death spans from P45-90. This heterogeneity in survival is consistent with other animal models of SUDEP 48–50 and reflects what human patients experience, whereby SUDEP risk is influenced by multiple factors including seizure frequency and age 5–8 . Furthermore, we demonstrate that atenolol, a cardiac-selective β-blocker, protected at-risk double mutant mice from premature death.…”

Section: Discussionsupporting

confidence: 86%

Atenolol reduces cardiac-mediated mortality in genetic mouse model of sudden unexpected death in epilepsy

Soh,

Kuanyshbek,

Mohamed Syazwan

et al. 2023

Preprint

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Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic cardiac risk factors, including loss-of-functionKCNH2variants, have been linked to SUDEP. We hypothesised that seizures and LQTS interact to increase SUDEP risk. To investigate this, we crossedKcnh2+/-andGabrg2R43Q/+mice that model LQTS and genetic epilepsy, respectively. Electrocorticography and electrocardiogram confirmed thatKcnh2+/-mice had a LQTS phenotype, whileGabrg2R43Q/+mice displayed spontaneous seizures. Double mutant mice (Kcnh2+/-/Gabrg2R43Q/+) had both seizure and LQTS phenotypes that were indistinguishable from the respective single mutant mice. Survival analysis revealed thatKcnh2+/-/Gabrg2R43Q/+mice experienced a disproportionate higher rate of seizure-related death. Long-term oral administration of atenolol, a cardiac-selective β-blocker, significantly improved survival in theKcnh2+/-/Gabrg2R43Q/+mice. Overall, the data implicates loss-of-functionKCNH2variants as an important risk factor, and the potential repurposing of β-blockers as a prevention strategy, for SUDEP in a subset of epilepsy patients.

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Section: Discussionsupporting

confidence: 86%

Atenolol reduces cardiac-mediated mortality in genetic mouse model of sudden unexpected death in epilepsy

Soh,

Kuanyshbek,

Mohamed Syazwan

et al. 2023

Preprint

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“…Consistent with these in vitro observations, both selective KCNT1 modulation by channel blockers 15 and oligonucleotide-mediated downregulation 16 were found to reverse epilepsy phenotypes in the P924L mouse model of KCNT1 epilepsy.…”

Section: Introductionsupporting

confidence: 74%

Functional evaluation of epilepsy‐associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties

et al. 2023

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ObjectiveGain of function variants in the sodium‐activated potassium channel KCNT1 have been associated with pediatric epilepsy disorders. Here, we systematically examine a spectrum of KCNT1 variants and establish their impact on channel function in multiple cellular systems.MethodsKCNT1 variants identified from published reports and genetic screening of pediatric epilepsy patients were expressed in Xenopus oocytes and HEK cell lines. Variant impact on current magnitude, current–voltage relationships, and sodium ion modulation were examined.ResultsWe determined basic properties of KCNT1 in Xenopus oocyte and HEK systems, including the role of extra‐ and intracellular sodium in regulating KCNT1 activity. The most common six KCNT1 variants demonstrated strong gain of function (GOF) effects on one or more channel properties. Analysis of 36 total variants identified phenotypic heterogeneity but a strong tendency for pathogenic variants to exert GOF effects on channel properties. By controlling intracellular sodium, we demonstrate that multiple pathogenic KCNT1 variants modulate channel voltage dependence by altering the sensitivity to sodium ions.SignificanceThis study represents the largest systematic functional examination of KCNT1 variants to date. We both confirm previously reported GOF channel phenotypes and expand the number of variants with in vitro GOF effects. Our data provide further evidence that novel KCNT1 variants identified in epilepsy patients lead to disease through generalizable GOF mechanisms including increases in current magnitude and/or current–voltage relationships.

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“…5,6 With a single exception, 7 all KCNT1 pathogenic variants display gain-of-function (GoF) properties. 8 Repurposed quinidine, 9 newly identified small-molecules, 10,11 or ASO-based gene silencing 12 have been proposed as precision medicine approaches for these patients.…”

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confidence: 99%

KCNT2‐Related Disorders: Phenotypes, Functional, and Pharmacological Properties

Cioclu

Mosca

Ambrosino

et al. 2023

Annals of Neurology

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Objective Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2‐related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. Methods Twenty‐five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole‐cell electrophysiology in HEK‐293 and SH‐SY5Y cells. Results The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in‐frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain‐of‐function (GoF), and 6 loss‐of‐function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. Interpretation We expanded the phenotypic and genotypic spectrum of KCNT2‐related disorders, highlighting novel genotype–phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332–349

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Antisense oligonucleotide therapy for KCNT1 encephalopathy

Cited by 20 publications

References 70 publications

Atenolol reduces cardiac-mediated mortality in genetic mouse model of sudden unexpected death in epilepsy

Atenolol reduces cardiac-mediated mortality in genetic mouse model of sudden unexpected death in epilepsy

Functional evaluation of epilepsy‐associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties

KCNT2‐Related Disorders: Phenotypes, Functional, and Pharmacological Properties

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