Gene replacement of alpha-globin with beta-globin restores hemoglobin balance in beta-thalassemia-derived hematopoietic stem and progenitor cells. Nature medicine Cromer, M. K., Camarena, J., Martin, R. M., Lesch, B. J., Vakulskas, C. A., Bode, N. M., Kurgan, G., Collingwood, M. A., Rettig, G. R., Behlke, M. A., Lemgart, V. T., Zhang, Y., Goyal, A., Zhao, F., Ponce, E., Srifa, W., Bak, R. O., Uchida, N., Majeti, R., Sheehan, V. A., Tisdale, J. F., Dever, D. P., Porteus, M. H. 2021


beta-Thalassemia pathology is due not only to loss of beta-globin (HBB), but also to erythrotoxic accumulation and aggregation of the beta-globin-binding partner, alpha-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 beta-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize beta-globin:alpha-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 beta-thalassemia.

View details for DOI 10.1038/s41591-021-01284-y

View details for PubMedID 33737751