Description du projet
Améliorer la manipulation génétique ex vivo des cellules souches hématopoïétiques
Les cellules souches hématopoïétiques (CSH) sont des cellules multipotentes capables de se différencier en n’importe quelle lignée hématopoïétique. Les approches de thérapie génique reposent toutefois sur une population cellulaire enrichie en CSH, car il n’est pas possible d’isoler ces cellules de manière prospective. Financé par le Conseil européen de l’innovation, le projet X-PAND propose de développer une plateforme ex vivo de culture, d’expansion et de génie génétique des CSH. X-PAND adoptera une approche à haut débit caractérisée par un délai d’exécution rapide, ce qui permettra d’optimiser les protocoles de thérapie génique sans avoir à mener de laborieuses expériences de transplantation in vivo chez la souris. Les chercheurs concentreront leurs recherches sur les syndromes héréditaires d’insuffisance médullaire et le cancer, mais ils prévoient d’étendre l’approche à d’autres maladies et de garantir l’aboutissement des thérapies géniques.
Objectif
Hematopoietic stem cells (HSC) are an elusive cell type, whose presence can only be inferred retrospectively, from the outcome of time-consuming transplantation experiments. Since current state-of-the-art does not allow prospective HSC identification, today’s cell and gene therapy technology has been mostly optimized on surrogate progenitor cells, which differ biologically from HSC. The technological breakthrough of this proposal is to capture HSC in the ex vivo culture, achieved by a combination of innovative expansion conditions, iterative cell sorting and multiomics single cell profiling. Rapid, quantitative and qualitative in vitro HSC assessment predictive of in vivo function may become a sustainable alternative to mouse xenotransplantation experiments. Applied to a state-of-the-art toolbox of genetic engineering technologies including clinically-proven lentiviral vectors as well as established and emerging targeted genome editing approaches, our in vitro HSC readout sets new standards in terms of throughput and turnaround time, allowing to efficiently test a multitude of HSC engineering conditions and tailor the most suitable technological approach to a specific disease or therapeutic application. This new precision-based approach to ex vivo HSC gene therapy will be applied to inherited bone marrow failure syndromes and cancer as paradigmatic examples where gene therapy may be used to correct a cell-intrinsic genetic defect or turn hematopoietic progeny into therapeutic vehicles provided with novel functions. Bringing together experts in cutting-edge gene editing technologies, ex vivo HSC manipulation, assessment of HSC responses to genetic engineering and bioinformatics analysis & integration of multi-dimensional single cell data will maximize the chances of delivering safer and more effective next-generation HSC-based gene therapy products, extending the reach of gene therapy to new disease contexts and making the outcome after gene therapy more predictable.
Champ scientifique
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineoncology
- medical and health sciencesclinical medicinetransplantation
- natural sciencesbiological sciencesgeneticsgenomes
Mots‑clés
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Thème(s)
Régime de financement
HORIZON-EIC - HORIZON EIC GrantsCoordinateur
20132 Milano
Italie