Enhancing the engraftment of ex-vivo genetically manipulated hematopoietic stem cells for the treatment of blood disorders

Hematopoietic stem cells (HSCs) are the most well characterised adult stem cell type and possibly the most widely used for therapeutic purposes. Over the past two decades, transplantation of HSCs genetically corrected ex-vivo through lentiviral gene therapy and, more recently, through genome editing has been successfully applied to the treatment of monogenic disorders of the blood and metabolic diseases in preclinical and clinical studies. However, some critical challenges are still hampering the full therapeutic potential of these platforms. Indeed, evidence, including our own, has highlighted the limited ability of gene therapy and, to a larger extent, of gene editing to correct multipotent and long-lived HSCs – capable of replenishing the hematopoietic system for the whole lifetime of an individual – and the reduced capacity of ex-vivo manipulated HSCs to engraft into the host bone marrow when transplanted. eGRAFT builds on the overarching hypothesis that the challenge of achieving therapeutic levels of gene correction in transplanted patients could be tackled by arming manipulated cells with an engrafting advantage that may operate through enhancement of their stemness, homing or survival when lodging into the bone marrow niche. By taking advantage of epigenome editing to modulate the expression of crucial HSC genes, advanced HSC-BM stroma interaction systems and unique access to highly performing gene transfer platforms and patient samples, we will comprehensively identify genetic components and strategies that enhance the engraftment of HSCs, which will be integrated into a one-size-fits-all platform for efficient ex-vivo manipulation of human HSCs for clincial purposes. eGRAFT is expected to fill a crucial knowledge and technological gap that will greatly impact on gene therapy and gene editing’s efficacy and feasibility, with the potential to benefit a large cohort of patients with hereditary blood disorders and hematological malignancies.