The silence of the mutant: towards a targeted therapy for KCNQ2-encephalopathy.

KCNQ2-encephalopathy (KCNQ2-E) is a subtype of severe epilepsy, characterized by neonatal seizures and a severe developmental impairment. The disorder is caused by mutations in KCNQ2. As in other epileptic encephalopathies (EEs), all currently available treatments purely target seizures, whereas the neurodevelopmental outcome is at least as devastating for the quality of life. There is thus a strong need for new therapies that target both aspects of the disease. We will perform an in vitro proof of concept study for RNA interference as a targeted treatment strategy for KCNQ2-E, using 2D neuronal cultures derived from human induced pluripotent stem cells (hiPSC), in which we aim to tackle both disease components. Since KCNQ2-E is proven to be caused by dominant-negative or gain-of-function variants, and KCNQ2-haploinsufficiency is known to cause a self-limiting neonatal epilepsy with normal development (Benign Familial Neonatal Epilepsy (KCNQ2-B)), mutant allele specific silencing seems a promising treatment approach. Using mutant specific short hairpin RNAs, we aim to revert the electrophysiological KCNQ2-E neuronal culture phenotype to the benign KCNQ2-B phenotype. In parallel, we will generate brain organoids to more precisely model and study the neurodevelopmental process and deficits in KCNQ2-E, and provide a more advanced screening model for future treatments. When successful, this approach could be extended to many other EEs with similar mutation characteristics.

Keywords:ENCEPHALOPATHY

Disciplines:Developmental neuroscience, Neurological and neuromuscular diseases

Project type:Collaboration project