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

In this project FRRB funds Partner number 1:

  • Ospedale San Raffaele – Divisione della Neuroscienza, Principal Investigator Dr. Vania Broccoli
Pathology of interest: Dravet syndrome
Area of research: Neurology
Start date: 1st June 2021
End date: 31st May 2024
Funding: € 318.800,00
Project partners:

  - Centre national de la recherche scientifique (CNRS) – Leading partner, France

  - University of Leuven, Belgium

  - Radboud University, NetherlandsUniversity of Tübingen, Germany


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.