Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) is proving successful to treat several genetic diseases. HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused, after the administration of toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells. We show that mobilizers create an opportunity for seamless engraftment of exogenous cells, which effectively outcompete those mobilized, to repopulate the depleted BM. The competitive advantage results from the rescue during ex vivo culture of a detrimental impact of mobilization on HSPCs and can be further enhanced by the transient overexpression of engraftment effectors exploiting optimized mRNA-based delivery. We show the therapeutic efficacy in a mouse model of hyper IgM syndrome and further developed it in human hematochimeric mice, showing its applicability and versatility when coupled with gene transfer and editing strategies. Overall, our findings provide a potentially valuable strategy paving the way to broader and safer use of HSPC-GT.

Automated summary

Hematopoietic stem/progenitor cell gene therapy has been successful in treating genetic diseases. Mobilizers provide an opportunity for exogenous cells to efficiently replace depleted bone marrow through competition. This competitive advantage is achieved by rescuing the detrimental effects of mobilization on hematopoietic stem/progenitor cells during ex vivo culture, and can be further enhanced by transient overexpression of engraftment effectors.