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

Description du projet

La découverte de cibles assistée par l’IA pour l’immunothérapie anticancéreuse

Le sous-type de cellules endothéliales (CE) présentant des signatures génétiques immunomodulatrices (IMEC) est important pour le développement d’immunothérapies alternatives. La désactivation des gènes immunosuppresseurs IMEC permet d’améliorer l’efficacité et de surmonter la résistance dans l’immunothérapie anticancéreuse. Le projet MystIMEC, financé par l’UE, entend valider 50 cibles CE et breveter cinq nouvelles cibles pour une immunothérapie alternative basée sur les IMEC. Le projet s’appuiera sur un outil d’IA déjà mis au point afin de prédire de nouvelles fonctions immunosuppressives pour les gènes endothéliaux et sur une technologie exclusive permettant de générer efficacement des souris knock-out spécifiques aux CE afin de valider les nouvelles cibles.

Objectif

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.

Coordinateur

VIB VZW
Contribution nette de l'UE
€ 3 498 426,00
Adresse
Rijvisschestraat 120
9052 Zwijnaarde - gent
Belgique

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Région
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Type d’activité
Research Organisations
Liens
Autres sources de financement
€ 0,00