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CRISPR/Cas9-mediated beta-globin (HBB) gene correction of sickle cell disease (SCD) patient-derived hematopoietic stem cells (HSCs) in combination with autologous transplantation represents a recent paradigm in gene therapy. Although several Cas9-based HBB-correction approaches have been proposed, functional correction of in vivo erythropoiesis has not been investigated previously. Here, we use a humanized globin-cluster SCD mouse model to study Cas9-AAV6-mediated HBB-correction in functional HSCs within the context of autologous transplantation. We discover that long-term multipotent HSCs can be gene corrected ex vivo and stable hemoglobin-A production can be achieved in vivo from HBB-corrected HSCs following autologous transplantation. We observe a direct correlation between increased HBB-corrected myeloid chimerism and normalized in vivo red blood cell (RBC) features, but even low levels of chimerism resulted in robust hemoglobin-A levels. Moreover, this study offers a platform for gene editing of mouse HSCs for both basic and translational research.

Original publication

DOI

10.1038/s41467-021-20909-x

Type

Journal article

Journal

Nat Commun

Publication Date

29/01/2021

Volume

12

Keywords

Anemia, Sickle Cell, Animals, CRISPR-Cas Systems, Combined Modality Therapy, Disease Models, Animal, Erythropoiesis, Female, Gene Editing, Gene Knock-In Techniques, Genetic Therapy, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Humans, Mice, Mice, Transgenic, Parvovirinae, Transplantation, Autologous, beta-Globins