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

Project description

AI-assisted target discovery for anticancer immunotherapy

The subtype of endothelial cells (EC) with immunomodulatory gene signatures (IMECs) is important for alternative immunotherapy development. The silencing of IMEC immunosuppressive genes provides opportunities to improve efficacy and overcome resistance in anticancer immunotherapy. The EU funded MystIMEC project aims to validate 50 EC targets and patent 5 new targets for alternative IMEC based immunotherapy. 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.

Objective

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.

Host institution

VIB VZW
Net EU contribution
€ 3 498 426,00
Address
SUZANNE TASSIERSTRAAT 1
9052 ZWIJNAARDE - GENT
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Total cost
€ 3 498 426,00

Beneficiaries (1)