5-Azacytidine Selectively Increases γ-Globin Synthesis in a Patient with β+ Thalassemia

5-Azacytidine is a cytidine analogue that is capable of activating repressed genes in tissue-culture cells and has been shown to increase hemoglobin-F production in anemic baboons. This drug was administered to a patient with severe β-thalassemia in an attempt to stimulate hemoglobin-F production. After seven days of 5-azacytidine treatment, γ-globin synthesis increased approximately sevenfold, temporarily normalizing the patient's unbalanced globin synthesis. Erythropoiesis became more effective, leading to a temporary increase in the absolute reticulocyte count (from 5000 to 22,000 per cubic millimeter) and in hemoglobin concentration (from 8.0 to 10.8 g per deciliter). Hypomethylation of bone-marrow DNA near both the γ-globin and ε-globin genes was directly demonstrated. At the time of peak drug effect, about 7000 γ-globin messenger RNA molecules were present per erythroid bone-marrow cell, in contrast to 10 to 15 ε-globin messenger RNA molecules per cell. 5-Azacytidine selectively increases γ-globin synthesis and therefore provides a new approach to the treatment of severe β-thalassemia. Further studies will be required to evaluate the efficacy, risks, and long-term toxicity of 5-azacytidine (or related compounds) before this approach can be used as a therapy for patients with disorders of hemoglobin synthesis. (N Engl J Med. 1982; 307:1469–75.) Beta-thalassemia is a disease characterized by decreased (β+) or absent (γ0) production of the β subunit of adult hemoglobin (hemoglobin A = α 2 β 2 ). Decreased synthesis of β globin results in a relative excess of α-globin molecules that precipitate and form inclusions in erythroid cells. These α-globin inclusions adversely affect erythroid-cell replication, membrane function, migration of cells from the marrow, and red-cell survival; these changes cause ineffective erythropoiesis, hemolysis, and severe anemia. Several molecular defects that cause β-thalassemia have recently been identified. 1 , 2 Deficient synthesis of β globin may be caused by mutations in the β-globin gene that . . .