Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy.

A missense mutation c.1220C>G of KCN2A gene was recently identified in an infant with epilepsy. KCNA2 encodes KV1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved PVP motif. Functional characterization revealed that mutant KV1.2_P407R subunits formed loss-of-function channels and suppressed both KV1.2 and KV1.1 channel activities. Hetero-tetrameric assembly of the KV1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human KV1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed KV1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.

Parents' priorities for decision-making of pediatric epilepsy treatments and perceived needs for decision support in multi-ethnic Asian clinical setting: A qualitative analysis.

OBJECTIVE: To identify parents' priorities when making a decision on genetic testing and antiseizure drug (ASD) options for pediatric epilepsy and their support needs for informed decision-making in multi-ethnic Asian clinical settings. METHODS: Qualitative in-depth interviews, using a semi-structured interview guide, were conducted with purposively selected parents of pediatric patients with newly diagnosed epilepsy or known diagnosis of epilepsy (n = 26). Interviews were audio recorded and transcribed verbatim. Thematic analysis was undertaken to generate themes. RESULTS: Parents' narratives showed difficulty assimilating information, while knowledge deficit and emotional vulnerability led parents' desire to defer a decision for testing and ASDs to mitigate decisional burden. Priorities for decisions were primarily based on intuitive ideas of the treatment's risks and benefits, yet very few could elaborate on tradeoffs between risks and efficacy. Priorities outside the purview of the healthcare team, such as children's emotional wellbeing and family burden of ASD administration, were also considered important. Authority-of-medical-professional heuristic facilitated the ASD decision for parents who preferred shared rather than sole responsibility for a decision. Importantly, parents' support needs for informed decision-making were very much related to the availability of support mechanisms in post-treatment decisions owing to perceived uncertainty of the chosen ASD. CONCLUSIONS: Findings suggest that multiple priorities influenced ASD decision process. To address support needs of parents for informed decision-making, more consideration should be given to post-treatment decision support through the provision of educational opportunities, building peer support networks, and developing a novel communication channel between healthcare providers and parents.