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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-02-0353.
Submitted February 4, 2002
Accepted June 12, 2002
Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo
Betty S Pace, Gary L White, George J Dover, Michael S Boosalis, Douglas V Faller, and Susan P Perrine*
Structural and Cell Biology, University of South Alabama, Mobile, AL, USA
Animal Resources, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA
Cancer Research Center, Boston University School of Medicine, Boston, MA, USA
* Corresponding author; email: sperrine{at}medicine.bu.edu.
Orally-bioactive compounds which induce  globin gene expression at tolerable doses are needed for optimal treatment of the ß-hemoglobinopathies. Short-chain fatty acids (SCFAs) of 2-6 carbons in length induce globin expression in animal models, and butyrate, phenylbutyrate, and valproate induce globin in human patients. However, the utility of these compounds is limited by requirements for large doses, due to their rapid metabolism, and by their tendency to inhibit cell proliferation, which limits the pool of erythroid progenitors in which globin can be induced. Selected short-chain fatty acid derivatives (SCFADs) were recently found to induce globin and also to stimulate proliferation of hematopoietic cells in vitro. These SCFADs were now evaluated in vivo in non-anemic transgenic mice containing the human ß globin gene locus and in anemic phlebotomized baboons. In mice treated with a SCFAD once daily for 5 days, globin mRNA increased 2-fold, reticulocytes increased 3 to 7-fold, and hematocrits increased by 27%. Administration of three SCFADs in anemic baboons increased F-reticulocytes 2-15-fold over baseline, and increased total hemoglobin by 1-2 gm/dl/week, despite ongoing significant daily phlebotomy. Pharmacokinetic studies demonstrated 90% oral bioavailability of two SCFADs, and targeted plasma levels were maintained for several hours after single oral doses equivalent to 10-20% of doses required for butyrate. These findings identify SCFADs which stimulate both globin gene expression and erythropoiesis in vivo, activities which are synergistically beneficial for treatment of the ß hemoglobinopathies, and useful for oral treatment of other anemias.
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