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CORDIS

Dissecting and targeting senescence programs to advance Hematopoietic Stem Cell-based gene therapies

Project description

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.

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.

Host institution

OSPEDALE SAN RAFFAELE SRL
Net EU contribution
€ 2 000 000,00
Address
VIA OLGETTINA 60
20132 Milano
Italy

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Region
Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 2 000 000,00

Beneficiaries (1)