AAV-KCNQ2

AAV-KCNQ2 is an experimental adeno-associated virus (AAV) gene therapy candidate designed for the treatment of KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE), a severe form of neonatal epilepsy. Developed by researchers at the California Institute of Technology, this therapy utilizes a neuronal-tropic AAV.CAP-B10 capsid to deliver a wild-type KCNQ2 transgene. To address the exceptionally narrow therapeutic window of KCNQ2, where both loss- and gain-of-function mutations cause disease, the construct incorporates a synthetic miRNA-based regulatory circuit termed DIMMER (Dosage-Invariant miRNA-Mediated Expression Regulators). This circuit uses an incoherent feed-forward loop design to achieve uniform, tunable neuronal expression of KCNQ2 that is independent of the viral dose at the single-cell level. Preclinical studies in mouse models have demonstrated that neonatal administration of AAV-KCNQ2 can reduce seizure susceptibility and improve cognitive performance, supporting its potential as a precision treatment for rare pediatric epilepsies requiring tight dosage control.