EnCRISPrx - A Permanent CRISPR-based Approach To Rescue Dravet Syndrome By Enhancing Scn1a Promoter Activity

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Dravet Syndrome is a severe catastrophic neurological disorder affecting young children. Every day 3 or 4 children are diagnosed with Dravet syndrome worldwide, with symptoms including epilepsy, autism, movement disorders and sleep disturbances. To date, the majority of therapies are ineffective or poorly tolerated. Sodium channel drugs which are otherwise effective in many forms of epilepsy may even worsen Dravet syndrome.In approximately 80% of cases, Dravet syndrome is caused by one of several hundred heterozygous mutations in a single gene, SCN1A, which result in loss of function. These are either spontaneous or inherited, and lead to insufficient expression of the protein. Our aim is to rescue all of these mutations with a single treatment that increases the expression of the protein. To do so, we propose to modify SCN1A gene to make it more active. We will increase the activity of both copies of the gene, but only the non-mutant one will make new proteins. We are aiming for a therapy that will restore the normal functioning of the brain, which is unlike conventional drugs that target proteins that underlie communication in the brain and can dampen activity overall. We will test several possible approaches in an animal model of Dravet Syndrome, using neuronal excitability, epilepsy and behavioural changes as readouts. This proposal will be useful not only for understand if a general treatment for Dravet syndrome is achievable, but also will give insight into the potential of these techniques to cure other neurological diseases caused by similar mutations in different genes. We stress that the approach proposed here is not gene editing as such, which can rescue only a single mutation at a time. Instead, we aim to correct the effects of all the mutations leading to a common pathology, and so the strategy can be generalized and have a substantial impact for a wide range of diseases that share a common genetic mechanism.