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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1790-1797
Sustained Induction of Fetal Hemoglobin by Pulse Butyrate Therapy in
Sickle Cell Disease
George F. Atweh,
Millicent Sutton,
Imad Nassif,
Vassiliki Boosalis,
George J. Dover,
Sylvan Wallenstein,
Elizabeth Wright,
Lillian McMahon,
George Stamatoyannopoulos,
Douglas V. Faller, and
Susan P. Perrine
From the Departments of Medicine, Pediatrics and Biomathematical
Sciences, Mount Sinai School of Medicine, New York, NY; the Departments
of Pediatrics, Medicine, Pharmacology, and Experimental Therapeutics,
Hemoglobinopathy-Thalassemia Research Unit, Boston University School of
Medicine, Boston, MA; the Department of Pediatrics, Johns Hopkins
University School of Medicine, Baltimore, MD; the Division of Medical
Genetics, University of Washington School of Medicine, Seattle, WA; and
The New England Research Institute, Watertown, MA.
High levels of fetal hemoglobin (Hb F) protect from many of the
complications of sickle cell disease and lead to improved survival.
Butyrate and other short chain fatty acids were previously shown to
increase Hb F production in erythroid cells in vitro and in animal
models in vivo. However, butyrates are also known to inhibit the
proliferation of many cell types, including erythroid cells. Experience
with the use of butyrate in animal models and in early clinical trials
demonstrated that the Hb F response may be lost after prolonged
administration of high doses of butyrate. We hypothesized that this
loss of response may be a result of the antiproliferative effects of
butyrate. We designed a regimen consisting of intermittent or pulse
therapy in which butyrate was administered for 4 days followed by 10 to
24 days with no drug exposure. This pulse regimen induced fetal globin
gene expression in 9 of 11 patients. The mean Hb F in this group
increased from 7.2% to 21.0% (P < .002) after intermittent
butyrate therapy for a mean duration of 29.9 weeks. This was associated
with a parallel increase in the number of F cells and F reticulocytes.
The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P < .006). The increased levels of Hb F
were sustained in all responders, including 1 patient who has been on
pulse butyrate therapy for more than 28 months. This regimen, which
resulted in a marked and sustained increase in Hb F levels in more than
two thirds of the adult sickle cell patients enrolled in this study,
was well tolerated without adverse side effects. These encouraging
results require confirmation along with an appropriate evaluation of
clinical outcomes in a larger number of patients with sickle cell disease.
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