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

Descripción del proyecto

Descubrimiento de dianas asistido por inteligencia artificial para la inmunoterapia antineoplásica

El subtipo de células endoteliales con firmas genéticas inmunomoduladoras (IMEC, por sus siglas en inglés) es importante para el desarrollo de inmunoterapias alternativas. Al silenciar los genes inmunosupresores de las IMEC, se puede mejorar la eficacia y superar la resistencia en la inmunoterapia antineoplásica. En el proyecto MystIMEC, financiado con fondos europeos, se pretende validar cincuenta dianas de células endoteliales y patentar cinco nuevas dianas para una inmunoterapia basada en IMEC. El equipo del proyecto aprovechará una herramienta de inteligencia artificial desarrollada previamente para predecir nuevas funciones inmunosupresoras de los genes endoteliales y una tecnología propia que permite generar de forma eficiente ratones con genes específicos de las células endoteliales desactivados para validar las nuevas dianas.

Objetivo

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. 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 unprece-dented 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 func-tional annotation / PubMed reports (comprising 30% of the human coding genome). We developed: (i) an innovative artificial intelligence (AI)-based tool (SCMYSTERYDENTIFIER) to predict new immunosuppres-sive functions for endothelial “mystery” genes; and (ii) 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.