High-level correction of the sickle mutation is amplified in vivo during erythroid differentiation
Wendy Magis, Mark A. DeWitt, Stacia K. Wyman, Jonathan T. Vu, Seok‐Jin Heo, Shirley Shao, Finn Hennig, Zulema Romero, Beatriz Campo-Fernández, Suzanne Saïd, Matthew McNeill, Garrett R. Rettig, Yongming Sun, Yu Wang, Mark A. Behlke, Donald B. Kohn, Dario Boffelli, Mark C. Walters, Jacob E. Corn, David I. K. Martin
Abstract
Background: A point mutation in sickle cell disease (SCD) alters one amino acid in the β-globin subunit of hemoglobin, with resultant anemia and multiorgan damage that typically shortens lifespan by decades. Because SCD is caused by a single mutation, and hematopoietic stem cells (HSCs) can be harvested, manipulated, and returned to an individual, it is an attractive target for gene correction. Results: erythroid differentiation markedly enriches for corrected β-globin alleles, indicating that erythroblasts carrying one or more corrected alleles have a survival advantage. Significance: These findings indicate that the sickle mutation can be corrected in autologous HSCs with an optimized protocol suitable for clinical translation.