Therapeutic strategies for Dravet syndrome: upregulation of endogenous SCN1A and modulation of pathological remodeling

Title	Therapeutic strategies for Dravet syndrome: upregulation of endogenous SCN1A and modulation of pathological remodeling
Acronym	SCN1A-UP!
Start date	2021-06-01
End date	2024-05-31
Sponsor	EJP Rare disease
Institution	Radboudumc Stem Cell Technology Center

Project Description

"Dravet syndrome (DS) is a rare, devastating encephalopathy of early childhood characterized by drug- resistant epileptic seizures, cognitive deficits and ataxia. DS is caused by loss-of-function mutations in SCN1A, encoding the main Na+ channel of GABAergic neurons (NaV1.1), which lead to widespread disinhibition of neuronal networks in mouse models that recapitulate DS phenotype and in patient-derived in vitro models. Although several anti-epileptic drugs are available they are only partially effective against seizures and not against other symptoms. The overall objective of SCN1A-UP! is to develop more effective treatments for DS by targeting directly the initial genetic dysfunction, SCN1A loss-of-function, as well as other signaling pathways leading to further pathological modifications in neuronal networks (pathological remodeling). 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 healthy (wild type) SCN1A allele by developing CRISPR-ON virally delivered techniques and screen for small molecule drugs, strategies for which we have already obtained a proof-of-concept; 2) Identify new signaling pathways to be targeted with small molecules or antisense oligonucleotides (ASOs), which can be implicated in pathological modifications of neuronal network functions. With this two-tiered strategy, we will maximize chances to identify genetic strategies and compounds that rescue in vitro and in vivo DS phenotypes. As these compounds can subsequently be transferred to (pre- ) clinical trials, SCN1A-UP forms a critical step in the development of treatment for DS and is therefore of utmost importance for DS patients and their families."