Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo.

Abstract

Orally bioactive compounds that induce gamma globin gene expression at tolerable doses are needed for optimal treatment of the beta-hemoglobinopathies. Short-chain fatty acids (SCFAs) of 2 to 6 carbons in length induce gamma globin expression in animal models, and butyrate, phenylbutyrate, and valproate induce gamma globin in human patients. The usefulness of these compounds, however, is limited by requirements for large doses because of their rapid metabolism and their tendency to inhibit cell proliferation, which limits the pool of erythroid progenitors in which gamma globin can be induced. Selected short-chain fatty acid derivatives (SCFADs) were recently found to induce gamma globin and to stimulate the proliferation of hematopoietic cells in vitro. These SCFADs are now evaluated in vivo in nonanemic transgenic mice containing the human beta globin gene locus and in anemic phlebotomized baboons. In mice treated with a SCFAD once daily for 5 days, gamma globin mRNA increased 2-fold, reticulocytes increased 3- to 7-fold, and hematocrit levels increased by 27%. Administration of 3 SCFADs in anemic baboons increased F-reticulocytes 2- to 15-fold over baseline and increased total hemoglobin levels by 1 to 2 g/dL per week despite ongoing significant daily phlebotomy. Pharmacokinetic studies demonstrated 90% oral bioavailability of 2 SCFADs, and targeted plasma levels were maintained for several hours after single oral doses equivalent to 10% to 20% of doses required for butyrate. These findings identify SCFADs that stimulate gamma globin gene expression and erythropoiesis in vivo, activities that are synergistically beneficial for treatment of the beta hemoglobinopathies and useful for the oral treatment of other anemias.

• Authors: Betty S Pace, Gary L White, George J Dover, Michael S Boosalis, Douglas V Faller, Susan P Perrine
• Journal: Blood (Blood) Vol. 100 Issue 13 Pg. 4640-8 (Dec 15 2002) ISSN: 0006-4971 [Print] United States
• PMID: 12393583 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fatty Acids, Volatile
• Phenylpropionates
• Recombinant Proteins
• alpha-methylhydrocinnamic acid
• Erythropoietin
• Globins
• Luciferases

Topics

• Anemia (genetics, metabolism)
• Animals
• Cells, Cultured (drug effects, metabolism)
• Chromosomes, Artificial, Yeast
• Drug Evaluation, Preclinical
• Erythroid Precursor Cells (cytology, drug effects)
• Erythropoiesis (drug effects)
• Erythropoietin (pharmacology)
• Fatty Acids, Volatile (pharmacokinetics, pharmacology)
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• Globins (biosynthesis, genetics)
• Half-Life
• Humans
• Luciferases (biosynthesis, genetics)
• Mice
• Mice, Transgenic
• Papio
• Phenylpropionates (pharmacology)
• Promoter Regions, Genetic
• Recombinant Proteins
• Reticulocyte Count
• Transfection