Toward gene therapy for Dravet syndrome: uncovering dynamics of reversibility and mechanisms of Scn1a gene modulation

Dravet Syndrome (DS) is a severe epilepsy that occurs in the first year of life with tonic-clonic seizures that evolve during the following years and are accompanied by motor, behavioral and cognitive disorders. It is caused by genetic defects in the SCN1A gene (it is sufficient that only one copy of the gene is altered to manifest the disease) which encodes for a component of the sodium channel Nav1.1, a protein essential for nervous cell activity, in particular for those with an inhibitory role in brain circuits, GABAergic interneurons. To date, no effective treatment is available for patients suffering from this disease. Innovative gene therapy approaches are being developed based on the super activation of the healthy copy of Scn1a gene, in order to make it produce all protein necessary to re-establish sufficient levels of inhibition in the circuits. However, important information on the degree of reversibility of the syndrome after restoring the physiological level of Nav1.1 is lacking. Furthermore, the molecular mechanisms that regulate the expression of the Scn1a gene are poorly understood. We will use a new mouse model of Dravet Syndrome, recently developed by our laboratory, to study the degree of reversibility of the disease after restoring the physiological levels of Nav1.1, when the symptoms are already manifested. In addition, we will carry out studies with advanced technologies on the gene promoter to clarify the interactions and factors that regulate the expression of the Scn1a gene in interneurons. This study will allow to collect observations on the reversibility of the DS and to clarify both the optimal time window for therapy delivery and the minimum number of neuronal cells to be corrected to have symptomatic amelioration. Furthermore, we will define new modulators of the expression of the Scn1a gene that could become targets of new therapies.