TREATKCNQ : Targeted treatment for KCNQ related encephalopathies: retigabine analogues, repurposed drugs and allele specific knock down

The KCNQ-encephalopathies (KCNQ-E) are a group of severe epilepsies with onset in the first months of life, characterized by treatment resistant seizures and developmental delay. They are caused by mutations in genes encoding a type of potassium channels, that normally act as “brakes” regulating brain excitability. Both a severe lack and excess of channel function can result in the development of KCNQ-E. Seizures in children with KCNQ-E often respond poorly to anti-epileptic drugs, and more importantly, therapies for the developmental problems are currently unavailable. With the aim to develop improved therapies for KCNQ-E, we will establish a consortium of researchers with expertise in KCNQ-related pathology and drug development, and access to a set of disease-relevant assays and disease models, such as fluorescence-based assays of potassium flux in cells, rodent and human neuronal cultures expressing KCNQ mutations, and mice modeling the characteristics of KCNQ-E. We will design and test safer and more potent analogues of retigabine, a drug that acts on KCNQ-channels but was recently withdrawn from the market due to side effects, and perform high-througput drug screening to identify novel openers and blockers of KCNQ channels. In parallel, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease-causing gene copy. Using this approach, we expect to provide pre-clinical evidence for different types of targeted treatments that have the potential to improve the developmental outcome of KCNQ-E.