Project description
Advancing ex vivo genetic manipulation of haematopoietic stem cells
Haematopoietic stem cells (HSCs) are multipotent cells that can differentiate into any haematopoietic lineage. However, gene therapy approaches rely on a cell population enriched in HSCs as these cells cannot be prospectively isolated. Funded by the European Innovation Council, the X-PAND project proposes to develop an ex vivo platform for the culture, expansion and genetic engineering of HSCs. The X-PAND approach will be high-throughput with a quick turnaround time, enabling the optimisation of gene therapy protocols without the need for laborious in vivo transplantation experiments in mice. Researchers will focus on inherited bone marrow failure syndromes and cancer, but the plan is to extend the approach to other diseases and secure the outcome of gene therapies.
Objective
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.
Fields of science
- 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
Keywords
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Topic(s)
Funding Scheme
HORIZON-EIC - HORIZON EIC GrantsCoordinator
20132 Milano
Italy