Author: ["M. Kyle Cromer","Joab Camarena","Renata M. Martin","Benjamin J. Lesch","Christopher A. Vakulskas","Nicole M. Bode","Gavin Kurgan","Michael A. Collingwood","Garrett R. Rettig","Mark A. Behlke","Viktor T. Lemgart","Yankai Zhang","Ankush Goyal","Feifei Zhao","Ezequiel Ponce","Waracharee Srifa","Rasmus O. Bak","Naoya Uchida","Ravindra Majeti","Vivien A. Sheehan","John F. Tisdale","Daniel P. Dever","Matthew H. Porteus"]
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Abstract
β-Thalassemia pathology is due not only to loss of β-globin (HBB), but also to erythrotoxic accumulation and aggregation of the β-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing β-thalassemia. A new genome editing strategy can normalize the β-globin:α-globin balance in human hematopoietic stem cells from patients with β-thalassemia and restore functional adult hemoglobin tetramers in patient-derived red blood cells.Cite this article
Cromer, M.K., Camarena, J., Martin, R.M. et al. Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells. Nat Med (2021). https://doi.org/10.1038/s41591-021-01284-y 