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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • M Kyle Cromer, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Joab Camarena, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Renata M Martin, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Benjamin J Lesch, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Christopher A Vakulskas, Integrated DNA Technologies
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  • Nicole M Bode, Integrated DNA Technologies
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  • Gavin Kurgan, Integrated DNA Technologies
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  • Michael A Collingwood, Integrated DNA Technologies
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  • Garrett R Rettig, Integrated DNA Technologies
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  • Mark A Behlke, Integrated DNA Technologies
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  • Viktor T Lemgart, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Yankai Zhang, Department of Medicine, Baylor College of Medicine
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  • Ankush Goyal, Department of Medicine, Baylor College of Medicine
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  • Feifei Zhao, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Ezequiel Ponce, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Waracharee Srifa, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Rasmus O Bak
  • Naoya Uchida, National Heart, Lung, and Blood Institute, National Institutes of Health
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  • Ravindra Majeti, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Vivien A Sheehan, Department of Medicine, Baylor College of Medicine
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  • John F Tisdale, National Heart, Lung, and Blood Institute, National Institutes of Health
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  • Daniel P Dever, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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  • Matthew H Porteus, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.

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.

Original languageEnglish
JournalNature Medicine
Volume27
Issue4
Pages (from-to)677-687
Number of pages11
ISSN1078-8956
DOIs
Publication statusPublished - Apr 2021

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