Precision Therapy in KCNQ2-Related Epilepsy

The two most common allelic diseases caused by genetic variants in KCNQ2 are either self-limited familiar neonatal epilepsy (KCNQ2-SLFNE) or neonatal onset developmental and epileptic encephalopathy (KCNQ2-NEO-DEE).[1] In this issue, Falsaperla et al present genotype–phenotype correlation and discuss tailored antiseizure medication (ASM) approaches for KCNQ2-related epilepsy. The results support previous findings revealing that sodium channel blockers and phenobarbital are the most commonly used and effective ASM for treatment of KCNQ2-associated conditions.[2] Epilepsy in KCNQ2-SLFNE is often self-limited. In contrast, patients with KCNQ2-NEO-DEE are usually severely affected suffering from frequent seizures refractory to ASM polytherapy and present with significant comorbidities including intellectual impairment and behavioural disturbances emphasizing the need for a precision therapy.

In recent years, a clear genotype–phenotype correlation could be established for KCNQ2-associated epilepsies. Whereas heterozygous loss-of-function variants (frameshift variants, nonsense variant, splice variants, and some missense variants) cause KCNQ2-SLFNE due to haploinsufficiency, missense variants with a dominant negative effect cause KCNQ2-NEO-DEE.[1] [3] Dominant negative mutations decrease potassium currents in neurons by more than 50% by affecting wild-type K_V7.2 (encoded by KCNQ2) and K_V7.3 (encoded by KCNQ2). The potassium channel opener retigabine (ezogabine in the United States) was approved in Europe in 2011 as an add-on therapy for focal seizures. Retigabine increases potassium currents by opening the K_V7.2 and K_V7.3 channels prompting its use as a potential precision therapy for patients with KCNQ2-NEO-DEE. In a first trial, 11 cases with KCNQ2-NEO-DEE were treated with ezogabine. It appeared to be well tolerated and potentially beneficial against refractory seizures, especially when started within the first 6 months of life.[4] More recently, eight patients with KCNQ2-NEO-DEE who received ezogabine were reported.[5] Half of the patients experienced more than 50% of sustained seizure reduction and two patients became seizure free. Eventually, developmental improvements were seen in all subjects, suggesting a disease modifying effect to some extent.

A phase 3 study (ClinicalTrials.gov Identifier: NCT04639310) of adjunctive ezogabine in pediatric cases with KCNQ2-NEO-DEE was started in 2021. Recruitment was prematurely terminated in May 2023 after inclusion of eight patients.

The use of antisense oligonucleotides (ASO) in DEE channelopathies associated with haploinsufficiency in order to increase the expression of the intact allele is not available in clinical routine so far but is under investigation in preclinical and clinical trials for some disorders (e.g., SCN1A-related epileptic disorders).[6] In contrast, ASO can be used to reduce the expression of proteins in a context of gain-of-function mutations (e.g., SCN2A-associated DEE).[7] ASO-based approaches are probably more challenging for KCNQ2-NEO-DEE as a dominant negative effect is more complex in its pathomechanism. Thus, therapeutic attempts would need to increase gene expression of the intact allele with a simultaneous knockdown of the mutant allele.

Taken together, the results of Falsaperla et al underline the urgent need for further development and introduction of precision-based therapies for KCNQ2-NEO-DEE. The occurrence of mutations with a dominant negative effect in KCNQ2-NEO-DEE may exhibit a more challenging pathomechanism to develop therapeutic strategies in comparison to other monogenetic DEEs. Although some encouraging results from preliminary case series of ezogabine arose, the premature termination of the pivotal phase 3 study suggests obstacles in the development and evaluation of drugs in this condition.

Publication History

Article published online:
18 September 2023

• References

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