Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease
Abstract Adenine base editing can convert sickle hemoglobin (HbS, βΕ6V) to G-Makassar hemoglobin (HbG, βE6A), a naturally occurring variant that is clinically asymptomatic. However, the quality and functionality of purified HbG and of mature HbGG and HbGS red blood cells (RBC) has not been assessed....
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56578-3 |
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| author | Zachary Kostamo Manuel A. Ortega Chavonna Xu Patricia R. Feliciano Elizabeth Budak Daisy Lam Valerie Winton Rebecca Jenkins Archita Venugopal Margaret Zhang John Jamieson Brent Coisman Kennedy Goldsborough Britney Hernandez Celeste K. Kanne Erica N. Evans Jordan Zgodny Yankai Zhang Jawa Darazim Ashwin Patel Michael A. Pendergast John Manis Adam J. Hartigan Giuseppe Ciaramella Seung-Joo Lee S. Haihua Chu Vivien A. Sheehan |
| author_facet | Zachary Kostamo Manuel A. Ortega Chavonna Xu Patricia R. Feliciano Elizabeth Budak Daisy Lam Valerie Winton Rebecca Jenkins Archita Venugopal Margaret Zhang John Jamieson Brent Coisman Kennedy Goldsborough Britney Hernandez Celeste K. Kanne Erica N. Evans Jordan Zgodny Yankai Zhang Jawa Darazim Ashwin Patel Michael A. Pendergast John Manis Adam J. Hartigan Giuseppe Ciaramella Seung-Joo Lee S. Haihua Chu Vivien A. Sheehan |
| author_sort | Zachary Kostamo |
| collection | DOAJ |
| description | Abstract Adenine base editing can convert sickle hemoglobin (HbS, βΕ6V) to G-Makassar hemoglobin (HbG, βE6A), a naturally occurring variant that is clinically asymptomatic. However, the quality and functionality of purified HbG and of mature HbGG and HbGS red blood cells (RBC) has not been assessed. Here, we develop a mouse model to characterize HbG. Purified HbG appears normal and does not polymerize under hypoxia. The topology of the hemoglobin fold with the βΕ6Α mutation is similar to HbA in the oxy and deoxy states. However, RBC containing HbGS are dehydrated, showing altered function and increased sickling under hypoxia. Blood counts and mitochondrial retention measures place HbGS RBCs as intermediate in severity between HbAS and HbSS, while organ function is comparable to HbAS. HbGG resembles HbAA for most metrics. Our results highlight the importance of functionally assessing the mature red cell environment when evaluating novel gene editing strategies for hematologic disorders. |
| format | Article |
| id | doaj-art-11ef113b172342b29d3cee6f6616f879 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-11ef113b172342b29d3cee6f6616f8792025-02-09T12:45:59ZengNature PortfolioNature Communications2041-17232025-02-0116111510.1038/s41467-025-56578-3Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell diseaseZachary Kostamo0Manuel A. Ortega1Chavonna Xu2Patricia R. Feliciano3Elizabeth Budak4Daisy Lam5Valerie Winton6Rebecca Jenkins7Archita Venugopal8Margaret Zhang9John Jamieson10Brent Coisman11Kennedy Goldsborough12Britney Hernandez13Celeste K. Kanne14Erica N. Evans15Jordan Zgodny16Yankai Zhang17Jawa Darazim18Ashwin Patel19Michael A. Pendergast20John Manis21Adam J. Hartigan22Giuseppe Ciaramella23Seung-Joo Lee24S. Haihua Chu25Vivien A. Sheehan26Emory University School of Medicine, Department of PediatricsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsEmory University School of Medicine, Department of PediatricsJoint Program in Transfusion Medicine, Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical SchoolBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsBeam TherapeuticsEmory University School of Medicine, Department of PediatricsAbstract Adenine base editing can convert sickle hemoglobin (HbS, βΕ6V) to G-Makassar hemoglobin (HbG, βE6A), a naturally occurring variant that is clinically asymptomatic. However, the quality and functionality of purified HbG and of mature HbGG and HbGS red blood cells (RBC) has not been assessed. Here, we develop a mouse model to characterize HbG. Purified HbG appears normal and does not polymerize under hypoxia. The topology of the hemoglobin fold with the βΕ6Α mutation is similar to HbA in the oxy and deoxy states. However, RBC containing HbGS are dehydrated, showing altered function and increased sickling under hypoxia. Blood counts and mitochondrial retention measures place HbGS RBCs as intermediate in severity between HbAS and HbSS, while organ function is comparable to HbAS. HbGG resembles HbAA for most metrics. Our results highlight the importance of functionally assessing the mature red cell environment when evaluating novel gene editing strategies for hematologic disorders.https://doi.org/10.1038/s41467-025-56578-3 |
| spellingShingle | Zachary Kostamo Manuel A. Ortega Chavonna Xu Patricia R. Feliciano Elizabeth Budak Daisy Lam Valerie Winton Rebecca Jenkins Archita Venugopal Margaret Zhang John Jamieson Brent Coisman Kennedy Goldsborough Britney Hernandez Celeste K. Kanne Erica N. Evans Jordan Zgodny Yankai Zhang Jawa Darazim Ashwin Patel Michael A. Pendergast John Manis Adam J. Hartigan Giuseppe Ciaramella Seung-Joo Lee S. Haihua Chu Vivien A. Sheehan Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease Nature Communications |
| title | Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease |
| title_full | Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease |
| title_fullStr | Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease |
| title_full_unstemmed | Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease |
| title_short | Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease |
| title_sort | base editing hbs to hbg makassar improves hemoglobin function supporting its use in sickle cell disease |
| url | https://doi.org/10.1038/s41467-025-56578-3 |
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