Objective
β-thalassemias and sickle cell disease (SCD) are caused by mutations in the β-globin gene (HBB) that result in the defective synthesis (β-thalassemias) or the production of an abnormal variant (SCD) of hemoglobin. Currently, the only curative option is allogeneic transplantation of hematopoietic stem cells (HSCs), but it is severely limited by conditioning toxicity and the restricted availability of compatible donors. Alternative strategies, based on lentiviral vector (LV)-mediated introduction of a functional copy of the HBB gene followed by autologous transplantation, are currently explored. Despite the fact that clinical data are promising, achieving a broad therapeutic benefit still remains a major hurdle because of inefficient gene correction and competition of the endogenous affected HSCs.
In this proposal, I intend to confer an in vivo competitive advantage to transduced HSCs in terms of homing and engraftment efficiencies by modulating the expression levels of the chemokine receptor CXCR4 through two different approaches. On one hand, as increased CXCR4 levels enhance bone marrow (BM) homing, I will develop an innovative LV-based strategy to transiently deliver CXCR4 into HSCs to improve their migration to the BM. On the other hand, as CXCR4 haploinsufficiency enhances proliferation of homed HSCs, I will develop LVs down-regulating CXCR4 expression to endow corrected HSCs with an increased BM repopulating capacity. Thanks to these strategies, corrected HSCs will be able to out-compete non-corrected as well as endogenous affected HSCs, thus attaining therapeutic levels of engraftment even with a reduced number of corrected HSCs. In addition, this will contribute to use a milder conditioning regimen, normally required to eliminate endogenous affected HSCs, and thus reduce its toxicity, which preclude this treatment for patients with high disease burden. Noteworthy, this approach can potentially benefit many diseases amenable to HSC gene therapy.
Fields of science (EuroSciVoc)
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.
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.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences medical biotechnology cells technologies stem cells
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine transplantation
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Keywords
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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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
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.
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
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.
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.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2017
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
75654 PARIS
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.