Nav1.1 translation enhancement-based therapy to treat Dravet Syndrome

Dravet Syndrome (DS) is a severe epileptic encephalopathy mainly caused by mutations in SCN1A gene that tipically affect and inactivate only one of two copies of the gene. We learned from animal models that the amount of functional sodium channel Na_v1.1 produced in this genetic condition is not sufficient for proper neuronal activity. Mutations impact mainly on GABAergic inhibitory interneurons that become less performing in regulating the activity of excitatory neurons. This unbalance in neuronal activity ultimately results in catastrophic seizures and behavioral alterations that cannot be successfully controlled by any therapy, determining a poor quality of life for patients and their families. Different gene therapy treatments based on the restoration of normal levels of functional Na_v1.1 protein are being developed and  they act mainly stimulating Scn1a gene expression at transcriptional level. In this project we propose to act downstream in the gene expression process and to increase the efficiency of Nav1.1 protein translation. This can be achieved optimizing sequences that are located in transcripts and controlling transduction efficiency. We will install permanent point mutations in these sequences in the brain of DS models by viral vectors and we will assess the effect on characteristic aspects of their phenotype including mortality and seizures.