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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-02-0353.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4640-4648
RED CELLS
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
From the Hemoglobinopathy-Thalassemia Research Unit,
Boston University School of Medicine, MA; the University of Oklahoma
Health Science Center, Oklahoma City; the University of South Alabama,
Mobile; and Johns Hopkins University School of Medicine, Baltimore, MD.
Orally bioactive compounds that induce  globin gene
expression at tolerable doses are needed for optimal treatment of the  -hemoglobinopathies. Short-chain fatty acids (SCFAs) of 2 to 6 carbons in length induce globin expression in animal models, and
butyrate, phenylbutyrate, and valproate induce 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 globin can be induced. Selected
short-chain fatty acid derivatives (SCFADs) were recently found to
induce 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 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 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 globin gene
expression and erythropoiesis in vivo, activities that are
synergistically beneficial for treatment of the hemoglobinopathies
and useful for the oral treatment of other anemias.
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