Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease

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 () and Vivien A. Sheehan ()
Additional contact information
Zachary Kostamo: Department of Pediatrics
Manuel A. Ortega: Beam Therapeutics
Chavonna Xu: Beam Therapeutics
Patricia R. Feliciano: Beam Therapeutics
Elizabeth Budak: Beam Therapeutics
Daisy Lam: Beam Therapeutics
Valerie Winton: Beam Therapeutics
Rebecca Jenkins: Beam Therapeutics
Archita Venugopal: Beam Therapeutics
Margaret Zhang: Beam Therapeutics
John Jamieson: Beam Therapeutics
Brent Coisman: Beam Therapeutics
Kennedy Goldsborough: Department of Pediatrics
Britney Hernandez: Department of Pediatrics
Celeste K. Kanne: Department of Pediatrics
Erica N. Evans: Department of Pediatrics
Jordan Zgodny: Department of Pediatrics
Yankai Zhang: Department of Pediatrics
Jawa Darazim: Department of Pediatrics
Ashwin Patel: Department of Pediatrics
Michael A. Pendergast: Department of Pediatrics
John Manis: Harvard Medical School
Adam J. Hartigan: Beam Therapeutics
Giuseppe Ciaramella: Beam Therapeutics
Seung-Joo Lee: Beam Therapeutics
S. Haihua Chu: Beam Therapeutics
Vivien A. Sheehan: Department of Pediatrics

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56578-3

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