A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders.
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.
Perrine
S P
SP
Children's Hospital Oakland Research Institute, Calif 94609.
Ginder
G D
GD
Faller
D V
DV
Dover
G H
GH
Ikuta
T
T
Witkowska
H E
HE
Cai
S P
SP
Vichinsky
E P
EP
Olivieri
N F
NF
D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002087:Butyrates / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D017086:beta-Thalassemia / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics
D002087:Butyrates; D012333:RNA, Messenger; D005914:Globins; D005319:Fetal Hemoglobin; D001120:Arginine; C033018:arginine butyrate