Developing gene therapy for the inherited childhood epilepsy, Dravet Syndrome (360G-Wellcome-207261_Z_17_Z)

Dravet syndrome is a rare, incurable epilepsy which affects young children. Before two years of age they have seizures, incoordination and cognitive impairment. They carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel NaV1.1. This protein is expressed in hippocampal inhibitory interneurons. Gene therapy offers several advantages over conventional drugs. It is a treatment which targets the cause of the disease by delivering the corrected copies of the SCN1A directly to brain cells. Our hypothesis is that we can incorporate a promoter to achieve persistent expression specifically in inhibitory interneurons of the hippocampus. We aim to compare two novel promoters against a pan-neuronal promoter, synapsin. The first is a truncated endogenous promoter, Gad67. The second is a synthetic promoter identified by in silico analysis. Before the project commences, we will clone these two promoters into lentiviral vectors. These, and a synapsin vector, will be injected intracranially into neonatal mice. At the start of the project the brains from four mice will be co-stained with antibodies directed against GFP and inhibitory interneurons to assess colocalisation. To measure persistence of expression from these promoters, the four remaining mice will be subject to whole-body bioluminescence imaging twice-weekly.