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

• Applicant: Dr. Ulrike Hedrich-Klimosch
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460762234

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.

• DFG Programme: Research Grants
• International Connection: Belgium, France, Italy, Netherlands
• Cooperation Partners: Professor Dr. Vania Broccoli; Dr. Massimo Mantegazza; Dr. Nael Nadif Kasri, Ph.D.; Dr. Peter de Witte