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Dissecting and targeting senescence programs to advance Hematopoietic Stem Cell...

Dissecting and targeting senescence programs to advance Hematopoietic Stem Cell based gene therapies 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, i... see more

28/02/2027

OSR

2M€

Project Budget: 2M€

Project leader

OSPEDALE SAN RAFFAELE SRL No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

PARTICIPATION DEPralty Sin fecha límite de participación.

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Financing granted El organismo H2020 notifico la concesión del proyecto The day 2021-07-24

ERC-2020-COG: ERC CONSOLIDATOR GRANTS Scope:Objectives

I+D

Cerrada does 5 years

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characteristics of the participant

Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

Private Information

No hay información privada compartida para este proyecto. Habla con el coordinador.

2 Participantes

OSR

2.00M€ | Leader

ECOLOGICA DELS PIRINEUS

497.11K€ | participant

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Project duration: 67 months Date Start: 2021-07-24
End date: 2027-02-28

Project leader

OSPEDALE SAN RAFFAELE SRL No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Project Budget 2M€

participation deadline Sin fecha límite de participación.

Project description 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.

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