Endothelial immunosuppressive mystery genes for alternative immunotherapy: artificial intelligence-driven target discovery and lipid nanoparticle/RNA-based target validation

Introduction

Compared to my previous Advanced ERC grants, this proposal is fundamentally different not only concerning its topic but also regarding its ambition to offer greater societal impact by coupling knowledge gain tighter to translation.

Objectives

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.

Methodology

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 immunosuppressive functions for endothelial “mystery” genes.
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 unprecedented scale in order to validate these targets.

Impact

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.

Future Applications

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.