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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 C, 2025. "Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56578-3
    DOI: 10.1038/s41467-025-56578-3
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    References listed on IDEAS

    as
    1. Gregory A. Newby & Jonathan S. Yen & Kaitly J. Woodard & Thiyagaraj Mayuranathan & Cicera R. Lazzarotto & Yichao Li & Heather Sheppard-Tillman & Shaina N. Porter & Yu Yao & Kalin Mayberry & Kelcee A. , 2021. "Base editing of haematopoietic stem cells rescues sickle cell disease in mice," Nature, Nature, vol. 595(7866), pages 295-302, July.
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