Project description
Boosting precision in gene editing
CRISPR gene editing allows scientists to modify DNA with unprecedented precision, offering great potential for correcting genetic diseases. Correction of the gene or targeted integration of a transgene occurs mainly through homology-directed repair (HDR). However, in hematopoietic stem and progenitor cells (HSPC) HDR is inefficient due to their cell cycle state and dominance of error-prone repair mechanisms. With the support of the Marie Skłodowska-Curie Actions programme, the ENRICHING-HDR project aims to resolve this issue through selective enrichment for cells that have successfully undergone HDR-editing. This approach will facilitate consistent therapeutic gene integration, offering a powerful new platform for safe and effective HSPC gene therapies.
Objective
"Hematopoietic stem and progenitor cell (HSPC) gene therapy involving viral vectors has shown remarkable promise in treating severe genetic disorders. The advent of gene editing technologies offers new possibilities for broadening the scope of HSPC gene therapy by enabling precise in situ gene correction or targeted transgene integration through homology-directed repair (HDR). However, HDR efficiency in HSPCs remains limited due to their cell cycle dynamics, suboptimal responses to the repair template, and the dominance of error-prone DNA repair pathways such as non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ), which negatively impact the engraftment of HDR-edited cells in vivo. This proposal aims to overcome these challenges by introducing an innovative ""purifying selection"" strategy. By using CRISPR/Cas9 to target essential genes that are haplo-insufficient in HSPCs, only cells undergoing HDR-mediated insertion of the gene of interest (GOI) will restore the function of the essential gene, while non-HDR edited cells will fail to recover, leading to their elimination. This selective enrichment of HDR-edited cells will dramatically enhance the precision and efficacy of gene editing. ENRICHING-HDR project will focus on identifying critical genes required for HSPC survival and maintenance through genome-wide CRISPR screening, selecting the most promising candidates for purifying selection, and evaluating the system's precision and platformability for clinical application. This project will establish a standardized platform for guide/nuclease reagents and template delivery, enabling reliable genomic integration and rapid adaptation of new therapeutic transgenes, streamlining the development of targeted therapies. The comprehensive training in advanced experimental techniques, research communication, and knowledge transfer will be instrumental in shaping my career trajectory, driving me toward my goal of becoming an independent researcher."
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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20132 Milano
Italy
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