Original Article
A Short-Term Trial of Butyrate to Stimulate Fetal-Globin-Gene Expression in the β-Globin Disorders
N Engl J Med 1993; 328:81-86January 14, 1993
- Abstract
Background
Fetal-globin (γ-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the β-globin chains that are defective or absent in patients with the β-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 γ-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 β-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 γ-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 γ-globin mRNA increased twofold to sixfold. The increase in γ-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 β-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate β-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 β-thalassemia.
Media in This Article
Figure 1
Fetal-Globin Synthesis before and after Short-Term Butyrate Treatment.Figure 2
γ-Globin Synthesis during Butyrate Treatment (Hatched Area) in a Seven-Year-Old Transfusion-Dependent Patient with Hemoglobin E and β0-Thalassemia (Patient 6).Article Activity
- Article
Sickle cell anemia and the β-thalassemia syndromes are prevalent disorders caused by mutations affecting the adult-globin (beta-globin) chain of hemoglobin A (the chains designated as α2β2)1-5. Sickle cell anemia was the first disease to be characterized at the molecular level3-5. Definitive treatment for the underlying condition has not followed, however, except for bone marrow transplantation in the few patients for whom there are appropriate donors. Increased production or prolonged expression of fetal globin (γ-globin) in sufficient quantities can ameliorate both disorders6-13. Chemotherapeutic agents, including azacitidine, cytarabine, and hydroxyurea, have been shown to stimulate γ-globin synthesis and fetal-hemoglobin production14-22. However, the cytotoxicity of these drugs poses some risk19. Recently, a national multicenter study of the natural history of sickle cell anemia, reported by Platt and colleagues,13 has led to a renewed search for safe, effective agents for stimulating the production of hemoglobin F. An increasing frequency of pain in adults with sickle cell anemia correlated with the risk of death, and any increment in the hemoglobin F concentration, even at low levels, had ameliorating effects13.
Infants who have high plasma levels of α-amino-n-butyric acid in the presence of maternal diabetes do not undergo the normal developmental gene switch from the production of predominantly γ-globin to that of β-globin before birth23. Such levels of α-amino-n-butyric acid did not delay other developmental processes in a large group of such infants, which suggested that butyric acid has a relatively safe and fairly specific effect in maintaining fetal-globin expression24. Butyrate stimulates a specific embryonic globin gene ρ in adult chickens through 5' flanking sequences25-27 and selectively stimulates the γ-globin gene in fetal sheep, cultured human erythroid cells, and adult nonhuman primates28-30. We and McDonagh and Nienhuis31 have found evidence that butyrate may act through sequences near the transcriptional start site to stimulate the activity of the human γ-globin-gene promoter24.
Butyrate has a low order of toxicity32-34. Children and adults with cancer have been treated with sodium butyrate as a differentiating agent (i.e., an agent altering cell maturation), and healthy adults and various animals have received sodium and arginine butyrate, with no major side effects32-34. In view of the evidence for selective stimulation of γ-globin by butyrate and the safety of administering this natural fatty acid to humans, we began a phase I trial of arginine butyrate in patients with β-hemoglobinopathies and β-thalassemia syndromes.
Methods
Patients and Treatment
Six patients with β-thalassemia or sickle cell anemia (three male and three female, 3 to 27 years old) were admitted to the hospital for intravenous butyrate treatment, with the approval of the institutional review board of Children's Hospital Oakland, the Food and Drug Administration, and the Health Protection Branch of the Department of Health and Welfare, Ontario, Canada. Two patients had β-thalassemia syndromes that required frequent red-cell transfusions. One patient with thalassemia intermedia who was homozygous for hemoglobin Lepore had multiple isoantibodies that had forced the discontinuation of regular blood transfusions. Occasional transfusions maintained her base-line hemoglobin concentration at 4.7 to 5.1 g per deciliter (2.9 to 3.2 mmol per liter); she had severe clinical manifestations, including borderline cardiac failure, growth retardation, and bone deformity due to massive bone marrow expansion. The globin-gene mutations in the patients with β-thalassemia were identified as previously described; the presence of hemoglobin Lepore was confirmed by electrospray mass spectrometry35,36. Sickle cell anemia (characterized by hemoglobin SS) was identified with the use of citrate agar and cellulose acetate electrophoresis. The patients' clinical profiles and β-globin mutations are shown in Table 1Table 1
Clinical Profiles and Responses of Six Patients with β-Hemoglobinopathies Treated with Arginine Butyrate..Arginine butyrate was prepared and approved by the FDA as a sterile nonpyrogenic solution that tested negative for mutagenicity. The drug was continuously infused with intravenous hydrating fluids at the rate of 500 mg per kilogram of body weight per day for seven days. If no side effects occurred, the rate was increased by 250 mg per kilogram per day to a final rate of 1500 mg per kilogram per day in four patients and a final rate of 2000 mg per kilogram per day in two patients. Plasma levels of butyrate were assayed by gas chromatography as described by McArthur and Sarnaik, and arginine levels were assayed with a Beckman amino acid analyzer (Beckman Instruments, Palo Alto, Calif.)37. Butyrate was administered to four of the patients for two weeks and to two of the patients for three weeks. Subsequently, prolonged compassionate use was allowed in the patient with thalassemia intermedia and hemoglobin Lepore; the drug was administered continuously at the highest infusion rate for nine days, then infused for nine hours per day, five days per week, for an additional five weeks.
Analysis of Globin Synthesis and F Reticulocytes
Heparin-treated blood samples were labeled with [3H]leucine (Amersham, Arlington Heights, Ill.) in leucine-free minimal essential medium (GIBCO, Grand Island, N.Y.) before and during treatment and weekly for two to four weeks after treatment. The ratios of globin synthesis were determined by column chromatography according to the method of Clegg et al38. The proportions of reticulocytes producing hemoglobin F (F reticulocytes) were measured as previously described20,39. Since four of the six patients received scheduled transfusions of packed red cells before or during treatment, their peripheral-blood levels of fetal globin were probably diluted by the normal blood they received, but samples were assayed by globin-chain electrophoresis as previously described26. Blood-chemistry values, complete blood counts, and coagulation profiles were monitored at least three times a week.
Analysis of Messenger RNA
The messenger RNA (mRNA) of γ-globin and β-globin was measured before and during butyrate treatment in the peripheral blood of two patients with thalassemia who had high proportions of circulating nucleated erythroblasts (three to seven nucleated erythroblasts per leukocyte) and in the bone marrow of one patient with sickle cell anemia. Nucleated cells were lysed in 4 mol of guanidinium thiocyanate (Fluka, St. Louis), 25 mmol of sodium citrate (pH 7.0), 0.5 percent sarcosyl (both from Fisher Scientific, San Jose, Calif.), and 0.1 mol of β-mercaptoethanol (Kodak, Rochester, N.Y.) per liter. Total cellular mRNA was isolated, and 10-μg samples were analyzed by slot blot hybridization to probes specific for human γ-globin and β-globin, as described by Constantoulakis et al.30 and Chomczynski and Sacchi40.
Results
This phase I-II treatment trial was conducted largely to determine the safety of doses of butyrate that could stimulate hemoglobin F production and to determine the responses of specific hematologic variables to a range of doses. Despite the short course of treatment, which represented only one or two cycles of erythroblast maturation, γ-globin synthesis increased significantly in all patients, from 6 to 45 percent above pretreatment levels (P<0.01 by paired t-test), regardless of the age of the patients and whether or not they had detectable γ-globin synthesis at the start of therapy (Figure 1Figure 1
Fetal-Globin Synthesis before and after Short-Term Butyrate Treatment.). Synthesis increased dramatically in a dose-dependent fashion in one patient, a severely affected transfusion-dependent seven-year-old boy with hemoglobin E and β0-thalassemia (Figure 2Figure 2γ-Globin Synthesis during Butyrate Treatment (Hatched Area) in a Seven-Year-Old Transfusion-Dependent Patient with Hemoglobin E and β0-Thalassemia (Patient 6).). An increase in the proportion of reticulocytes synthesizing hemoglobin F was the first change detected, particularly in the patients whose pretreatment levels of γ-globin synthesis were low (Table 1). The increases in the percentage of F reticulocytes did not appear to be dose-dependent and continued in two patients monitored for one month without therapy, although fetal-globin synthesis returned to base-line levels rapidly. The percentage of F reticulocytes in the patient who was homozygous for hemoglobin Lepore was 99 percent before treatment and therefore could not increase. While this patient was receiving 1500 mg of arginine butyrate per kilogram per day, the total γ-globin synthesis increased and the imbalance in the ratio of non-α-globins to α-globin improved, rising from 0.3 to 0.8. Taken together, the results in these patients demonstrated that butyrate induced both an increase in the proportion of cells producing hemoglobin F and an increase in total γ-globin produced per cell. The ratio of α-globin to non-α-globin improved with treatment in the patients with thalassemia major and thalassemia intermedia, resulting in globin-chain ratios characteristic of mild β-thalassemia intermedia and thalassemia trait, respectively6. The levels of γ-globin mRNA increased twofold to sixfold (Figure 3Figure 3
Autoradiogram of Blots of Total Cellular mRNA from Patients before and during Butyrate Treatment, Hybridized with γ-Specific or β-Specific Probes.). The absolute amount of γ-globin mRNA in each blood sample could not be directly compared with the amount of β-globin mRNA, because the γ and β probes were labeled at different specific activities. However, levels of γ-globin mRNA increased during butyrate therapy in all three patients with thalassemia. Plasma free hemoglobin levels fell at the beginning of therapy in the two adults with β-thalassemia, suggesting that the increase in γ-globin chains and the improvement in the globin-chain ratio reduced hemolysis (Figure 4Figure 4
Plasma Free Hemoglobin Concentrations before and during Butyrate Treatment in Two Adult Patients with Thalassemia (Patients 4 and 5) Who Had Not Received Recent Transfusions before the Start of Treatment.). Subsequent prolonged butyrate treatment in the patient with hemoglobin Lepore increased the ratio of non-α-globins to α-globin to 1.0 during a continuous infusion of 2000 mg per kilogram per day, and to 0.8 with nine hours of treatment per day at this dosage. The ratio decreased to about half the base-line value of 0.6 within 12 to 48 hours after butyrate therapy was stopped. Although effective therapy was given for only nine hours daily for five weeks, the hemoglobin level rose from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter) (Figure 5Figure 5
Hemoglobin Concentrations in a Patient with Thalassemia Treated with Butyrate Infusions Intermittently for Seven Weeks (Patient 5).).Minimal side effects were observed during treatment. A patient with sickle cell anemia had a transient, slight rise in serum aminotransferase concentrations that occurred concomitantly with a viral infection and that may have represented a manifestation of increased sickling-related hemolysis or viral disease. The concentration of blood urea nitrogen, although not that of creatinine, rose briefly in this patient and in one other at the end of the three-week infusion, but it returned to normal within 12 hours after therapy was discontinued. This resolution was probably due to the well-described effects of arginine on ureagenesis34. Transient anorexia developed in one patient. No side effects were observed in the patient who received treatment for seven weeks.
Butyrate was detected at levels of about 0.01 mmol per liter in the urine of two of the three patients with sickle cell anemia during infusion, although not in the urine of the three patients with thalassemia. These concentrations averaged 20 to 25 percent of plasma levels and were higher than those reported in previous studies, in which less than 0.2 percent of the butyrate in plasma appeared in the urine34. The urinary loss of butyrate in the patients with sickle cell anemia may have reflected the higher glomerular filtration rate and decreased tubular reabsorption that have been observed in such patients41. The highest plasma butyrate concentration in the patients with β-thalassemia was 0.05 mmol per liter, and that in the patients with sickle cell anemia was 0.04 mmol per liter. Butyrate was undetectable within 15 minutes after the infusion was discontinued. Arginine was also cleared rapidly from the plasma; levels fell to half of those recorded during infusion within 15 minutes after therapy ended and to base-line levels within 12 hours. The levels of arginine detected in the urine of the patients with sickle cell anemia (16,000 to 67,000 nmol per milligram of creatinine) were higher than those in the urine of patients with β-thalassemia (17 to 1900 nmol per milligram of creatinine). This difference may reflect the protein-losing nephropathy of sickle cell anemia41.
Discussion
The results of this pilot trial indicate that butyrate may be a potent agent for enhancing hemoglobin F production. Pharmacologic stimulation of fetal globin is an appealing approach to ameliorating β-globin disorders. Patients with hereditary persistence of fetal hemoglobin have no adverse effects from the lifelong production of hemoglobin F. Saudi Arabian and Indian patients with sickle cell anemia, whose proportion of hemoglobin F is typically at least 25 percent, have mild or benign sickle cell disease9-12. Accordingly, attempts to increase the expression of fetal globin in patients with β-globin diseases have used agents that influence the growth kinetics of erythroid cells, such as inducing acceleration of erythropoiesis so that more red cells are produced from earlier erythroid progenitors, which synthesize higher levels of hemoglobin F,42-44 or have used chemotherapeutic agents, which may involve some degree of bone marrow suppression14-19. Hydroxyurea frequently produces its greatest effects after six months of treatment20,22.
The brief phase I-II trial that we have described represents an attempt to use a natural fatty acid that selectively stimulates the human γ-globin-gene promoter in experimental systems and the natural model of delayed globin-gene switching that occurs in infants with high plasma levels of α-amino-n-butyric acid23,24,28. Despite the low plasma concentrations of butyrate detected in our patients, their short course of butyrate therapy resulted in a remarkably rapid stimulation of γ-globin expression. Their F-reticulocyte levels increased within three days, and their fetal-globin synthesis increased significantly within two weeks, reaching levels previously reported to ameliorate both disorders. It is noteworthy that with butyrate treatment, the levels of γ-globin synthesis in the patients with sickle cell disease were within the range of levels in Saudi Arabian patients with sickle cell anemia, who have benign disease because their mean level of γ-globin synthesis in reticulocytes is 8 percent and their proportion of hemoglobin F in peripheral blood is above 20 percent10. When the dose of butyrate was increased to 2000 mg per kilogram per day and treatment was extended for an additional week, fetal-globin synthesis rose further in a dose-dependent fashion, after reaching a plateau with the starting dose. In the patients with thalassemia so treated, high plasma levels of free hemoglobin, a manifestation of the marked hemolysis in β-thalassemia, fell abruptly as the increase in γ-globin synthesis began to reduce the excess of unmatched α-globin chains that are characteristic of the disease. The rapid increase in fetal-globin synthesis that occurred, despite negligible plasma concentrations of butyrate during the first week of treatment, suggests an unusual sensitivity of the human fetal-globin gene to stimulation by this agent or to one of its metabolic byproducts.
The dramatic responses in γ-globin-gene expression in the patients with β-hemoglobinopathies described here indicate that the administration of arginine butyrate represents a novel and potentially effective therapy for these prevalent molecular disorders. The models on which butyrate treatment is based, and previous clinical experience, indicate that it has few short-term side effects. Further trials of orally bioavailable, long-acting derivatives of butyrate and longer courses of treatment with butyrate in the higher doses given to our patients appear warranted to evaluate long-term efficacy and tolerance in larger groups of patients.
Supported by grants (HL-37118 and HL-20895) from the National Heart, Lung, and Blood Institute, a grant (DK-29902) from the National Institute of Diabetes and Digestive and Kidney Diseases, a grant (RR-06505-01) from the National Institutes of Health, and a grant-in-aid from the American Heart Association, California Division, with funds contributed by the Alameda County Chapter. Dr. Olivieri is a career scientist of the Ontario Ministry of Health.
We are indebted to the FDA, particularly Drs. S. Fredd, L. Talerico, and A. Shaw and Mrs. Bronwyn Collier, and to Thomas Richmond for assistance in the preparation of the drug; to the pharmacy staff, nurses, and house staff of the Children's Hospital Oakland and the Hospital for Sick Children; to YuXin Jin, Abbie Mays, Nancy Wandersee, Steven Lee, Su-Ting Li, and Wendy Su for technical assistance; and to Sherry Seybold for assistance in the preparation of the manuscript.
Source Information
From the Children's Hospital Oakland Research Institute, Oakland, Calif. (S.P.P., H.E.W., E.P.V.); the Hospital for Sick Children, Toronto (N.F.O.); the University of Minnesota School of Medicine, Minneapolis (G.D.G.); Boston University School of Medicine, Boston (D.V.F.); Howard Hughes Medical Institute, University of California, San Francisco (T.I., S.C.); and Johns Hopkins University School of Medicine, Baltimore (G.H.D.).
Address reprint requests to Dr. Perrine at Children's Hospital Oakland Research Institute, Rm. 115, 747 52nd St., Oakland, CA 94609.
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