ISOBUTYRAMIDE, AN ORALLY BIOAVAILABLE BUTYRATE ANALOG, STIMULATES FETAL GLOBIN GENE-EXPRESSION IN-VITRO AND IN-VIVO

Butyrate and other short-chain fatty acids stimulate fetal globin gene expression and have potential for ameliorating the beta globin disord ers. Butyrate, however, is rapidly metabolized in vivo and reaches onl y micromolar concentrations in plasma. We report here that a branched- chain derivative of butyrate, isobutyramide, increases gamma globin ge ne expression in cultured human erythroid progenitors in vitro and sti mulates activity from a minimal gamma globin gene promoter linked to a reporter gene in stable and transient expression assays, with slightl y less activity in these in vitro assays than butyrate. In vivo, admin istration of isobutyramide to anaemic adult baboons rapidly stimulates fetal globin synthesis and F-reticulocyte production. Plasma concentr ations at millimolar levels are achieved after a single intravenous or oral dose (500-600 mg/kg), and these concentrations are maintained fo r 9.5-10.5 h. These results indicate that although isobutyramide has s lightly 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 re activating fetal globin gene expression in vivo.