The project will capitalise on a previously developed AI-based tool to predict new immunosuppressive functions for endothelial genes and a proprietary technology that enables the efficient generation of EC-specific knockout mice to validate the new targets.

Project description

This Advanced ERC grant proposal has the ambition to offer greater societal impact by coupling knowledge gain tighter to translation. It promises to obtain new insights in an understudied endothelial cell (EC) subtype with immunomodulatory gene signatures (coined “IMECs”), highly relevant for alternative immunotherapy development. Indeed, silencing immunosuppressive genes in IMECs offers unprecedented opportunities to improve the efficacy of and to overcome the resistance to current anti-cancer immunotherapy, to which the immunosuppressive tumor endothelium contributes.

To identify previously unknown/unmined (“virgin”) drug targets, we also focus on “mystery” genes, lacking functional annotation / PubMed reports (comprising 30% of the human coding genome).

We developed:

1. an innovative artificial intelligence (AI)-based tool (SCMYSTERYDENTIFIER) to predict new immunosuppres-sive functions for endothelial “mystery” genes; and
2. a revolutionizing (“REVOLT”) technology (based on injecting EC-selective lipid nanoparticles containing sgRNA in mice expressing Cas9 selectively in ECs) to generate EC-specific knockout mice rapidly (days)/inexpensively (300€/mouse) at an unprece-dented scale in order to validate these targets. Demystifying the mystery genome offers formidable opportunities for knowledge gain and therapy development.

We will validate 50 new EC targets and aspire to identify and patent 5 previously unknown targets for alternative IMEC-based immunotherapy. The SCMYSTERYDENTIFIER tool can be made generic to discover any type of function for mystery genes in any cell type, while the REVOLT technology promises to revolutionize the pace of genetic research in the vascular biology field, offering formidable impact for the research community in academia and pharma.