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

Abstract

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 beta-thalassemia in an attempt to stimulate hemoglobin-F production. After seven days of 5-azacytidine treatment, gamma-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 gamma-globin and epsilon-globin genes was directly demonstrated. At the time of peak drug effect, about 7000 gamma-globin messenger RNA molecules were present per erythroid bone-marrow cell, in contrast to 10 to 15 epsilon-globin messenger RNA molecules per cell. 5-Azacytidine selectivity increases gamma-globin synthesis and therefore provides a new approach to the treatment of severe beta-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.

Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease

“…Its ability to stimulate HbF production was also demonstrated in a small number of patients with SCD and β-thalassemia. 5,6 Treatment with 5-azacytidine resulted in a significant increase in the level of HbF that was associated with a decrease in the fraction of dense cells in patients with SCD. Treatment with this drug also led to a partial correction of the non-α:α chain imbalance and a decrease in transfusion requirements in few patients with β-thalassemia.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…These observations stimulated the development of clinical trials of 5-azacytidine in a small number of sickle cell anemia and β-thalassemia patients. These trials showed that 5-azacytine treatment elicited in these patients an increase of HbF synthesis and reduced the level of anemia [88,97,98].…”

“…5-Azacytidine (5-Aza) was the first agent able to reactivate HbF synthesis in humans used for the treatment of β-thalassemia [88] and sickle cell disease [89] patients. The mechanism through which 5-Aza stimulates HbF synthesis is unclear.…”

Hydroxyurea in sickle cell disease: What will it take to change practice?

“…Appreciation of the role of DNA methylation in gene silencing led to the use of 5-azacytidine, an inhibitor of methyltransferase, to induce fetal hemoglobin (HbF) production in baboons and later in patients with SCD and b-thalassemia [1][2][3]. Although 5-azacytidine was shown to be an effective inducer of HbF in patients with b-thalassemia and SCD, large-scale clinical trials with this agent were never performed because of concerns over its potential toxicities.…”