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

Journal article

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.

Authors: Wilkinson, AC; Dever, DP; Baik, R; Camarena, J; Hsu, I

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 12
• Issue: 1
• Pages: 686-686
• Article number: 686
• Publication date: 2021-01-29
• DOI: 10.1038/s41467-021-20909-x
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Globin; Genetic enhancement; Cell biology; Ex vivo; Immunology; Erythropoiesis; Gene; Myeloid; In vivo; Medicine; Genetics; Internal medicine; Anemia; Cancer research; Transplantation; Haematopoiesis; Stem cell; Biology; CRISPR; Context (archaeology)