Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo

Abstract

Summary. Butyrate and other short-chain fatty acids stimulate fetal globin gene expression and have potential for ameliorating the β globin disorders. Butyrate, however, is rapidly metabolized in vivo and reaches only micromolar concentrations in plasma. We report here that a branched-chain derivative of butyrate, isobutyramide, increases γ globin gene expression in cultured human erythroid progenitors in vitro and stimulates activity from a minimal γ globin gene promoter linked to a reporter gene in stable and transient expression assays, which slightly less activity in these in vitro assays than butyrate. In vivo, administration of isobutyramide to anaemic adult baboons rapidly stimulates fetal globin syntesis and F-reticulocyte production. Plasma concentrations at millimolar levels are achieved after a single intravenous or oral dose (500–600 mg/kg), and these concentrations are maintained for 90.5–10.5h. These results indicate that although isobutyramide has slightly less activity than butyrate in vitro in enhancing fetal globin expression at the cellular and molecular level, its prolonged in vivo half-life may provide superior activity as a therapeutic agent for reactivating fetal globin gene expression in vivo.