SCN1A-up! : Therapeutic strategies for Dravet syndrome: upregulation of endogenous SCN1A and modulation of remodeling

Dravet syndrome (DS) is a rare, devastating encephalopathy of early childhood characterized by drug-resistant epileptic seizures, cognitive deficits and ataxia. DS is initially caused by loss-of-function mutations in SCN1A encoding the main Na+ channel of GABAergic neurons that lead to widespread disinhibition in mouse models recapitulating DS. Later pathologic remodelling can modify other signalling pathways. Available treatments are only partially effective against seizures. The overall objective of SCN1A-up! is to develop more effective treatments for DS with a bottom up approach, targeting SCN1A loss of function, the primary cause of the disease, and pathologic remodeling that can develop at later stages, therapeutic concepts that could be applied also to other diseases. An effective disease-preventing or -modifying treatment for DS will most likely need a polytherapy with different approaches and drugs. To fulfil this challenging task, we will develop two complementary strategies: 1) Increase expression levels of the wild type SCN1A allele (patients are heterozygous) by developing CRISP-ON virally delivered techniques (classic gene therapy does not allow delivery of the large SCN1A gene) and screen for small molecule drugs, strategy for which we have already obtained a proof of concept; 2) Identify new signaling pathways to be targeted with drugs, which may be implicated in pathologic remodeling. All approaches will be tested and validated extensively in vitro and in vivo in animal and human models, and we will test synergistic effects and model polytherapy.