Project description DEENESFRITPL Overcoming senescence in hematopoietic gene therapy Gene therapy for a variety of hematopoietic conditions entails the ex vivo genetic manipulation of hematopoietic stem and progenitor cells (HSPCs) and their transplantation back into the patient. Emerging evidence indicates that current gene transfer and gene editing technologies trigger the DNA damage response pathway and lead to cell cycle arrest and senescence, hampering the hematopoietic reconstitution potential of engineered HSPCs. The EU-funded ReviveSTEM project aims to identify the molecular determinants responsible for HSPC senescence and examine ways to overcome them towards more efficient and safer gene therapy applications. Show the project objective Hide the project objective Objective The success of Hematopoietic Stem and Progenitor Cell (HSPC) gene therapies critically depends on the capacity to genetically engineer HSPCs without compromising their functional properties. Emerging evidence, including our own, indicates that HSPC exposure to currently available gene transfer and gene editing technologies –which require prolonged ex-vivo culture, high viral vector doses and nuclease-induced DNA double strand breaks– unexpectedly converge on the DNA damage response (DDR), a signaling cascade leading to cell cycle arrest. Protracted DDR impairs the hematopoietic reconstitution of gene-modified cells upon transplantation; instead, its transient inhibition significantly improves their functionality. This experimental evidence uncovers a previously unappreciated interplay between viral vector sensing and the host cell DDR machinery in human HSPCs. Yet, we have just scratched the surface of a plethora of still unexplored cellular programs potentially hampering the clonal composition and the dynamics of reconstitution upon transplantation of this primitive cell compartment. This proposal builds on the innovative concept that current gene engineering protocols may inadvertently trigger the activation of a cellular senescence program in HSPCs with both cell-autonomous and paracrine short- and long-term consequences on engineered human hematopoiesis. By employing quantitative imaging and cutting-edge genomic technologies and taking advantage of uniquely available gene therapy platforms and primary patient samples, we will identify the molecular determinants that promote senescence in HSPCs and design innovative hypothesis-driven strategies to mitigate senescence barriers for more effective, safer and clinically broader gene therapy applications. Successful completion of the project will unveil a new set of mechanisms controlling the biology of gene-engineered HSPCs and open novel scientific horizons for the development of innovative gene and cell therapies. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicinetransplantationmedical and health sciencesmedical biotechnologycells technologies Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-COG - ERC CONSOLIDATOR GRANTS Call for proposal ERC-2020-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Coordinator OSPEDALE SAN RAFFAELE SRL Net EU contribution € 2 000 000,00 Address Via olgettina 60 20132 Milano Italy See on map Region Nord-Ovest Lombardia Milano Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all OSPEDALE SAN RAFFAELE SRL Italy Net EU contribution € 2 000 000,00 Address Via olgettina 60 20132 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
