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A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.

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.

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  • Authors+Show Affiliations

    ,

    Children's Hospital Oakland Research Institute, Calif 94609.

    , , , , , , ,

    Source

    The New England journal of medicine 328:2 1993 Jan 14 pg 81-6

    MeSH

    Adolescent
    Adult
    Anemia, Sickle Cell
    Arginine
    Butyrates
    Child
    Child, Preschool
    Female
    Fetal Hemoglobin
    Globins
    Humans
    Infusions, Intravenous
    Male
    RNA, Messenger
    beta-Thalassemia

    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 - https://www.nejm.org/doi/10.1056/NEJM199301143280202?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=www.ncbi.nlm.nih.gov DB - PRIME DP - Unbound Medicine ER -