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. doi: 10.1056/NEJM199301143280202.


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.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Anemia, Sickle Cell / blood*
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / genetics
  • Arginine / administration & dosage
  • Arginine / analogs & derivatives*
  • Arginine / therapeutic use
  • Butyrates / administration & dosage
  • Butyrates / therapeutic use*
  • Child
  • Child, Preschool
  • Female
  • Fetal Hemoglobin / biosynthesis
  • Globins / biosynthesis*
  • Globins / genetics
  • Humans
  • Infusions, Intravenous
  • Male
  • RNA, Messenger / analysis
  • beta-Thalassemia / blood*
  • beta-Thalassemia / drug therapy*
  • beta-Thalassemia / genetics


  • Butyrates
  • RNA, Messenger
  • Globins
  • Fetal Hemoglobin
  • Arginine
  • arginine butyrate