Prevention and gene therapy of viral encephalitis using specific interferon-stimulated genes – ISG-therapy

Novel strategies are required to fight viruses that invade the brain. Viral infections elicit an innate immune response mediated by type I interferons (IFNs), in turn inducing hundreds of IFN-stimulated genes (ISGs). Despite their broad antiviral efficacy, IFN usage is limited in the clinic because of adverse effects, notably in the brain.
We hypothesize that targeted expression of a well-chosen subset of ISGs would provide protection of the brain while minimizing side effects. We will implement this strategy in animal models.
First, an in vivo overexpression screen of ~60 ISGs will be conducted in zebrafish. This large cell type-specific in vivo screen will be made possible thanks to a novel CRISPR-based method with broad potential applications. After expression in neurons or glia, innocuity and antiviral protection will be assessed.
Then, the best hits will be tested in mice in vitro and in vivo using AAV gene transfer to target ISG expression to brain cells, and their antiviral properties tested with neuroinvasive virus with RNA+, RNA- and DNA genomes.