Cas9-AAV6 gene correction of beta-globin in autologous HSCs improves sickle cell disease erythropoiesis in mice

Adam C. Wilkinson (), Daniel P. Dever, Ron Baik, Joab Camarena, Ian Hsu, Carsten T. Charlesworth, Chika Morita, Hiromitsu Nakauchi () and Matthew H. Porteus ()
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Adam C. Wilkinson: Stanford University School of Medicine
Daniel P. Dever: Stanford University School of Medicine
Ron Baik: Stanford University School of Medicine
Joab Camarena: Stanford University School of Medicine
Ian Hsu: Stanford University School of Medicine
Carsten T. Charlesworth: Stanford University School of Medicine
Chika Morita: Stanford University School of Medicine
Hiromitsu Nakauchi: Stanford University School of Medicine
Matthew H. Porteus: Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20909-x

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