IMPROVING HEMATOPOIETIC STEM CELL- BASED GENE THERAPY OUTCOME BY MODULATING CXCR4 EXPRESSION

Información del proyecto

CXCR4THERAPY

Identificador del acuerdo de subvención: 798591

DOI

10.3030/798591

Proyecto finalizado el 31 Diciembre 2019

Fecha de la firma de la CE 18 Abril 2018

Fecha de inicio 1 Junio 2018

Fecha de finalización 31 Mayo 2020

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 173 076,00

Aportación de la UE

€ 173 076,00

Coordinado por

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Objetivo

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.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › biotecnología médica › ingeniería genética › terapia génica
• ciencias médicas y de la salud › biotecnología médica › tecnologías celulares › células madre
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › medicina clínica › trasplante

Palabras clave

• CXCR4
• ex vivo HSC correction
• gene therapy
• multi-functional LV-particles
• engraftment

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2017 - Individual Fellowships
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2017

Coordinador

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

• Aportación neta de la UEn: € 173 076,00
• Dirección: RUE DE TOLBIAC 101 ; 75654 PARIS ; Francia
• Tipo de actividad: Research Organisations
• Coste total: € 173 076,00