– BEATKCNQ

Childhood-onset epilepsy (COE) poses significant challenges including therapy resistance and co-morbid cognitive and behavioural issues. Mutations in KCNQ2 and KCNQ3, encoding Kv7.2 and Kv7.3 voltage gated potassium channel subunits, are common in COE. Variants in these genes manifest diverse epileptic disorders, from Self-Limiting Familial Neonatal Epilepsy to treatment-resistant epilepsy and intellectual disability. Non-seizure comorbidities are prevalent, highlighting the need for comprehensive treatment approaches. KCNQ2/3 mutations can have loss-of-function, dominant negative and gain-of-function effects on the current, and these seem to correlate with clinical phenotype and prognosis. There is a rationale that Kv7 openers and blockers might be precision medicine strategies, but there is a lack of clinical validation of this hypothesis. The BEATKCNQ initiative aims to transform KCNQ2/3-related disorders by leveraging advanced technologies. Objectives include: 1. Enhancing molecular and diagnostic accuracy using in silico and machine learning tools to predict variant effects and refine trial stratification methods; 2. Identifying repurposed drugs via in vitro patient-specific stem cell models using an innovative network based approach, fostering personalized medicine approaches; 3. Discovering biomarkers using in vivo EEG analysis to predict outcomes and treatment responses, thereby facilitating patient-centric care; and 4. Conducting pilot n-of-1 trials to assess efficacy of repurposed drugs, advancing precision medicine efforts. The project seeks to improve outcomes for children grappling with these debilitating disorders through precision medicine approaches and biomarker discovery efforts, ultimately revolutionizing the landscape of KCNQ2/3-related disorders.