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- Title
Cas9-AAV6 gene correction of beta-globin in autologous HSCs improves sickle cell disease erythropoiesis in mice.
- Authors
Wilkinson, Adam C.; Dever, Daniel P.; Baik, Ron; Camarena, Joab; Hsu, Ian; Charlesworth, Carsten T.; Morita, Chika; Nakauchi, Hiromitsu; Porteus, Matthew H.
- Abstract
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. CRISPR mediated gene correction of sickle cell disease (SCD) in patient-derived hematopoietic stem cells is a promising avenue for therapy. Here the authors use a humanized SCD mouse model to study gene editing in the context of autologous transplantation.
- Subjects
SICKLE cell anemia; GENES; FETAL hemoglobin; GENOME editing; HEMATOPOIETIC stem cells; ERYTHROPOIESIS; AUTOTRANSPLANTATION
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-20909-x