The Fetal-to-Adult Hemoglobin Switch — Mechanism and Therapy

Orkin, Stuart H. M.D.

¹Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston Children’s Hospital, Boston
²Department of Pediatrics, Harvard Medical School and Howard Hughes Medical Institute, Boston

Dr. Orkin can be contacted at [email protected] or at Boston Children’s Hospital, Karp Family Research Bldg., 1 Blackfan Circle, Boston, MA 02115.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

Franklin H. Epstein, M.D., served the New England Journal of Medicine for more than 20 years. A keen clinician, accomplished researcher, and outstanding teacher, Dr. Epstein was Chair and Professor of Medicine at Beth Israel Deaconess Medical Center, Boston, where the Franklin H. Epstein, M.D., Memorial Lectureship in Mechanisms of Disease has been established in his memory.

New England Journal of Medicine 392(21):p 2135-2149, June 5, 2025. | DOI: 10.1056/NEJMra2405260

Key Points

Fetal Globin Reactivation for Hemoglobinopathies

The major hemoglobin disorders, β-thalassemia and sickle cell disease, represent a large and growing global health burden.
Molecular research has elucidated the mechanism controlling the developmental switch from fetal hemoglobin (HbF) to adult hemoglobin (HbA).
BCL11A, the principal switch factor, which was identified through genomewide association studies, directly represses the fetal globin (γ-globin) gene promoter; this repression silences the expression of γ-globin in adulthood.
Gene editing of an essential erythroid-specific enhancer within BCL11A reduces BCL11A expression, which permits reactivation of HbF. This strategy was used in clinical trials involving patients with β-thalassemia or sickle cell disease and resulted in the first approved editing therapies.
Gene-based therapies for hemoglobin disorders are not suited to the treatment of large numbers of patients. Research is needed to develop safe and effective in vivo genetic therapy or mechanism-based, targeted small-molecule drugs.

Fetal β-Globin Deregulation for Hemoglobinopathies

The switch from fetal γ-globin to adult β-globin is controlled by BCL11A. Genetic manipulation of BCL11A improves disease outcomes by turning γ-globin expression back on to compensate for mutant β-globin.