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 newspaper › Journal article › Research › peer-review
DOI
- https://doi.org/10.1038/s41591-021-01284-y
Final published version
- 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. ,
- 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. ,
- 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. ,
- 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. ,
- Christopher A Vakulskas, Integrated DNA Technologies ,
- Nicole M Bode, Integrated DNA Technologies ,
- Gavin Kurgan, Integrated DNA Technologies ,
- Michael A Collingwood, Integrated DNA Technologies ,
- Garrett R Rettig, Integrated DNA Technologies ,
- Mark A Behlke, Integrated DNA Technologies ,
- 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. ,
- Yankai Zhang, Department of Medicine, Baylor College of Medicine ,
- Ankush Goyal, Department of Medicine, Baylor College of Medicine ,
- 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. ,
- 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. ,
- 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. ,
- Rasmus O Bak
- Naoya Uchida, National Heart, Lung, and Blood Institute, National Institutes of Health ,
- 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. ,
- Vivien A Sheehan, Department of Medicine, Baylor College of Medicine ,
- John F Tisdale, National Heart, Lung, and Blood Institute, National Institutes of Health ,
- 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. ,
- 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 language | English |
|---|---|
| Journal | Nature Medicine |
| Volume | 27 |
| Issue | 4 |
| Pages (from-to) | 677-687 |
| Number of pages | 11 |
| ISSN | 1078-8956 |
| DOIs | |
| Publication status | Published - Apr 2021 |
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