Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells
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 treatm...
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Elsevier
2025-01-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472401492X |
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| author | 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 |
| author_facet | 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 |
| author_sort | Simon N. Chu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bb096df3b6dc447b87361221593d24f6 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-bb096df3b6dc447b87361221593d24f62025-01-05T04:27:56ZengElsevierCell Reports2211-12472025-01-01441115141Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cellsSimon N. Chu0Eric Soupene1Devesh Sharma2Roshani Sinha3Travis McCreary4Britney Hernandez5Huifeng Shen6Beeke Wienert7Chance Bowman8Han Yin9Benjamin J. Lesch10Kun Jia11Kathleen A. Romero12Zachary Kostamo13Yankai Zhang14Tammy Tran15Marco Cordero16Shota Homma17Jessica P. Hampton18James M. Gardner19Bruce R. Conklin20Tippi C. MacKenzie21Vivien A. Sheehan22Matthew H. Porteus23M. Kyle Cromer24Department 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, USADepartment of Pediatrics, University of California, San Francisco, Oakland, CA 94609, USADepartment 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, USADepartment 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, USADepartment 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, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USAGladstone Institutes, San Francisco, CA 94158, USADepartment 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, USADepartment of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USADepartment 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, USADepartment 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, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USADepartment 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, USADepartment 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, USADepartment of Genetics, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Stanford University, Stanford, CA 94305, USADepartment of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USAGladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USADepartment 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, USAAflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30329, USADepartment of Pediatrics, Stanford University, Stanford, CA 94305, USADepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472401492XCP: Stem cell research |
| spellingShingle | 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 Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells Cell Reports CP: Stem cell research |
| title | Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells |
| title_full | Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells |
| title_fullStr | Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells |
| title_full_unstemmed | Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells |
| title_short | Dual α-globin-truncated erythropoietin receptor knockin restores hemoglobin production in α-thalassemia-derived erythroid cells |
| title_sort | dual α globin truncated erythropoietin receptor knockin restores hemoglobin production in α thalassemia derived erythroid cells |
| topic | CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S221112472401492X |
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