Cell Reports (Jan 2025)
Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells
- Simon N. Chu,
- Eric Soupene,
- Devesh Sharma,
- Roshani Sinha,
- Travis McCreary,
- Britney Hernandez,
- Huifeng Shen,
- Beeke Wienert,
- Chance Bowman,
- Han Yin,
- Benjamin J. Lesch,
- Kun Jia,
- Kathleen A. Romero,
- Zachary Kostamo,
- Yankai Zhang,
- Tammy Tran,
- Marco Cordero,
- Shota Homma,
- Jessica P. Hampton,
- James M. Gardner,
- Bruce R. Conklin,
- Tippi C. MacKenzie,
- Vivien A. Sheehan,
- Matthew H. Porteus,
- M. Kyle Cromer
Affiliations
- Simon N. Chu
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Eric Soupene
- Department of Pediatrics, University of California, San Francisco, Oakland, CA 94609, USA
- Devesh Sharma
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Roshani Sinha
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Travis McCreary
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Britney Hernandez
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Huifeng Shen
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Beeke Wienert
- Gladstone Institutes, San Francisco, CA 94158, USA
- Chance Bowman
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Han Yin
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Benjamin J. Lesch
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Kun Jia
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Kathleen A. Romero
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Zachary Kostamo
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Yankai Zhang
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Tammy Tran
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Marco Cordero
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Shota Homma
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
- Jessica P. Hampton
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
- James M. Gardner
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Bruce R. Conklin
- Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
- Tippi C. MacKenzie
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Vivien A. Sheehan
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USA
- Matthew H. Porteus
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
- M. Kyle Cromer
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
- Journal volume & issue
-
Vol. 44,
no. 1
p. 115141
Abstract
Summary: The most severe form of α-thalassemia results from loss of all four copies of α-globin. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to the imbalance of β-globin and α-globin chains. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for α-thalassemia. To address this, we designed a Cas9/AAV6-mediated genome editing strategy that integrates a functional α-globin gene into the β-globin locus in α-thalassemia patient-derived hematopoietic stem and progenitor cells (HSPCs). Incorporation of a truncated erythropoietin receptor transgene into the α-globin integration cassette significantly increased erythropoietic output from edited HSPCs and led to the most robust production of α-globin, and consequently hemoglobin tetramers. By directing edited HSPCs toward increased production of clinically relevant erythroid cells, this approach has the potential to mitigate the limitations of current treatments for the hemoglobinopathies, including low genome editing and low engraftment rates.
