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A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.
N Engl J Med 1993; 328(2):81-6NEJM

Abstract

BACKGROUND

Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin--gene expression in the developing fetus, cultured cells, and animal models.

METHODS

To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment.

RESULTS

In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P < 0.01). The proportion of F reticulocytes increased about twofold, and the level of gamma-globin mRNA increased twofold to sixfold. The increase in gamma-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations.

CONCLUSIONS

In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia.

Authors+Show Affiliations

Children's Hospital Oakland Research Institute, Calif 94609.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7677966

Citation

Perrine, S P., et al. "A Short-term Trial of Butyrate to Stimulate Fetal-globin-gene Expression in the Beta-globin Disorders." The New England Journal of Medicine, vol. 328, no. 2, 1993, pp. 81-6.
Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med. 1993;328(2):81-6.
Perrine, S. P., Ginder, G. D., Faller, D. V., Dover, G. H., Ikuta, T., Witkowska, H. E., ... Olivieri, N. F. (1993). A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. The New England Journal of Medicine, 328(2), pp. 81-6.
Perrine SP, et al. A Short-term Trial of Butyrate to Stimulate Fetal-globin-gene Expression in the Beta-globin Disorders. N Engl J Med. 1993 Jan 14;328(2):81-6. PubMed PMID: 7677966.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. AU - Perrine,S P, AU - Ginder,G D, AU - Faller,D V, AU - Dover,G H, AU - Ikuta,T, AU - Witkowska,H E, AU - Cai,S P, AU - Vichinsky,E P, AU - Olivieri,N F, PY - 1993/1/14/pubmed PY - 1993/1/14/medline PY - 1993/1/14/entrez SP - 81 EP - 6 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 328 IS - 2 N2 - BACKGROUND: Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin--gene expression in the developing fetus, cultured cells, and animal models. METHODS: To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment. RESULTS: In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P < 0.01). The proportion of F reticulocytes increased about twofold, and the level of gamma-globin mRNA increased twofold to sixfold. The increase in gamma-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations. CONCLUSIONS: In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia. SN - 0028-4793 UR - https://www.unboundmedicine.com/medline/citation/7677966/A_short_term_trial_of_butyrate_to_stimulate_fetal_globin_gene_expression_in_the_beta_globin_disorders_ L2 - http://www.nejm.org/doi/full/10.1056/NEJM199301143280202?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -