A Short-Term Trial of Butyrate to Stimulate Fetal-Globin-Gene Expression in the β-Globin Disorders

Background: Fetal-globin (γ-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the β-globin chains that are defective or absent in patients with the β-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in γ-globin-gene expression in the developing fetus, cultured cells, and animal models. Methods: To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with β-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of γ-globin messenger RNA (mRNA) were determined before and during treatment. Results: In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P<0.01). The proportion of F reticulocytes increased about twofold, and the level of γ-globin mRNA increased twofold to sixfold. The increase in γ-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations. Conclusions: In patients with β-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate β-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or β-thalassemia., Sickle cell anemia and the β-thalassemia syndromes are prevalent disorders caused by mutations affecting the adult-globin (beta-globin) chain of hemoglobin A (the chains designated as α₂β₂)¹–⁵. Sickle cell anemia was the first disease to be characterized at the molecular level³–⁵. Definitive treatment for the underlying condition has not followed, however, except for bone marrow transplantation in the few patients for whom there are appropriate donors. Increased production or prolonged expression of fetal globin (γ-globin) in sufficient quantities can ameliorate both disorders⁶–¹³. Chemotherapeutic agents, including azacitidine, cytarabine, and hydroxyurea, have been…