DSynchro

Dravet syndrome (DS) is a severe childhood epilepsy caused by haploinsufficiency of SCN1A. SCN1A encodes NaV1.1, the alpha subunit of a type I voltage-gated sodium channel. A significant decrease in NaV1.1 activity generates an imbalance between brain excitation and inhibition that causes DS comorbidities. The lack of efficacy of conventional (pharmacologic) anti-epileptic drugs, and the long impact on the patient and their families are significant financial and emotional burdens. Of note, 73% of children with DS die before their 10th birthday. Therefore, alternative therapies are needed. Due to haploinsufficiency, etiological approaches such as gene therapy could significantly improve the life of children with DS. The cornerstone for clinical gene transfer is the perfection of vector design, efficacy, delivery, and expression kinetics. The greatest challenges that dominate therapy for neurodevelopmental disease are 1) targeting the correct population of cells (neurons, astrocytes, microglia) in the desired structure(s), 2) repair of neuronal functions, 3) maintaining healthy and corrected cells alive in potentially toxic environments, 4) modifying enough cells to make a clinical impact, and/or 5) maintaining therapeutic levels of expression for decades. For three years, we have been developing a gene replacement approach for DS. In spite of not modifying the principal deficit in inhibitory neurons, we nonetheless demonstrated a significant impact on the reductions of febrile and spontaneous seizures, and increased life span of mice with DS. DSynchro addresses fundamental and translational aspects of DS therapy by modifying vector designs to target expression in inhibitory neurons, test the therapeutic outcome and understand the changes in network synchronicity induced by exogenous NaV1.1 activity. Our consortium, which includes expertise in vector development, gene transfer to the brain, electrophysiology, DS physiopathology, and clinical therapy, is ideally suited to develop an innovative therapy for DS.