Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease
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.
Authors
- Patrícia R. Feliciano
- Manuel Gabriel Trauco Ortega
- Elizabeth Budak
- Erica N Evans
- Alex Pendergast (ORCID: https://orcid.org/0009-0000-3560-0290)
- Valerie J. Winton
- Amudha L. Venugopal
- Rebecca Jenkins
- Kennedy Goldsborough (ORCID: https://orcid.org/0000-0001-9403-2721)
- John J. Jamieson
- Giuseppe Ciaramella (ORCID: https://orcid.org/0000-0003-3339-7211)
- M. Zhang
- Ashwin Patel (ORCID: https://orcid.org/0000-0003-0075-3304)
- Chavonna Xu
- Vivien Sheehan (ORCID: https://orcid.org/0000-0003-2837-2255)
- John Manis (ORCID: https://orcid.org/0000-0002-3630-778X)
- Britney Hernandez (ORCID: https://orcid.org/0000-0003-1913-2073)
- Brent Coisman
- S. Haihua Chu (ORCID: https://orcid.org/0000-0002-8333-5409)
- Adam J. Hartigan
- Celeste K. Kanne (ORCID: https://orcid.org/0009-0002-0547-905X)
- Zachary Kostamo
- Jawa Darazim
- Jordan Zgodny
- Seung‐Joo Lee (ORCID: https://orcid.org/0000-0001-5916-9888)
- Yankai Zhang (ORCID: https://orcid.org/0009-0001-2938-3581)
- Daisy Lam
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Emory University (US)
- Beam Therapeutics (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1038/s41467-025-56578-3
- Citations
- 9
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 14.63
Funders
- U.S. Department of Energy
- National Institutes of Health
- Office of Science
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- Biological and Environmental Research
- Brookhaven National Laboratory