Gene replacement of α-globin with β-globin restores hemoglobin balance in β-thalassemia-derived hematopoietic stem and progenitor cells

Nat Med. 2021 Apr;27(4):677-687. doi: 10.1038/s41591-021-01284-y. Epub 2021 Mar 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Sickle Cell / pathology
  • Animals
  • Antigens, CD34 / metabolism
  • Dependovirus / genetics
  • Erythrocytes / metabolism
  • Gene Editing
  • Genes, Reporter
  • Genetic Loci
  • Genetic Therapy*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / metabolism*
  • Hemoglobins / metabolism*
  • Humans
  • Mice
  • Promoter Regions, Genetic / genetics
  • alpha-Globins / genetics*
  • beta-Globins / genetics*
  • beta-Thalassemia / genetics*
  • beta-Thalassemia / therapy*


  • Antigens, CD34
  • Hemoglobins
  • alpha-Globins
  • beta-Globins