Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells.
Cell
; 185(13): 2248-2264.e21, 2022 06 23.
Article
em En
| MEDLINE
| ID: mdl-35617958
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transplante de Células-Tronco Hematopoéticas
/
Edição de Genes
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Itália