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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is considerable interest in identifying nontoxic differentiation inducers for the treatment of various malignant and nonmalignant blood disorders, including inborn beta-chain hemoglobinopathies. Using the human leukemic K562 cell line as a model, we explored the efficacy of phenylacetate, an amino acid derivative with a low toxicity index when administered to humans. Treatment of K562 cultures with pharmacologically attainable concentrations of phenylacetate resulted in erythroid differentiation, evident by the reduced growth rate and increased hemoglobin production. The effect was time- and dose-dependent, further augmented by glutamine starvation (phenylacetate is known to deplete circulating glutamine in vivo), and reversible upon cessation of treatment. Molecular analysis showed that phenylacetate induced gamma globin gene expression with subsequent accumulation of the fetal form of hemoglobin (HbF). Interestingly, the addition of phenylacetate to antitumor agents of clinical interest, eg, hydroxyurea and 5-azacytidine, caused superinduction of HbF biosynthesis. The results suggest that phenylacetate, used alone or in combination with other drugs, might offer a safe and effective new approach to treatment of some hematopoietic neoplasms and severe hemoglobinopathies.
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PMID:Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. 138 30

Blood erythroid progenitors (BFU-E) from patients with sickle and thalassemic syndromes were compared with those from normal individuals. The day of maximal colony formation in methyl cellulose was slightly later in the cultures from the patients with hemoglobinopathies than in the normal cultures. The number of colonies/100,000 mononuclear cells was similar in all cultures on day 13, but was higher in the hemoglobinopathy cultures on the day of maximal growth. The number of BFU-E/mL of blood was significantly higher than normal at all times in both sickle cell anemia and thalassemia. The proportional synthesis of gamma globin was twice normal in all sickle cultures, and 4 times normal in those from beta+-thalassemia. Hemin and interleukin-3 increased the numbers of erythroid colonies in all cultures, but did not consistently alter the globin synthesis patterns. Each progenitor population has a unique pattern in terms of time course, number of BFU-E, and level of gamma globin synthesis. These features indicate distinct types of BFU-E, or differences in accessory cells, or both, which distinguish blood-borne erythropoiesis in normals and those with hemoglobinopathies.
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PMID:Sickle and thalassemic erythroid progenitor cells are different from normal. 148 17

Molecular mechanisms involved in control of globin gene expression are a prominent target in current basic biologic research. A better understanding of these mechanisms might also impinge on a clinical goal: amelioration of the human hemoglobinopathies. Recent reports have established the coexistence of embryonic and adult globins in rodent yolk-sac erythroid cells, raising the possibility that globin ontogeny takes place in these cells. The present study was undertaken to define the extent of this putative ontogenic process. We measured daily rates of synthesis of individual globins in hamster yolk-sac erythroid cells from the earliest day in gestation that these cells are available (day 7) until the day they cease to replicate (day 13). Converted to a per-cell basis, the rates demonstrate an ontogenic progression in globin synthesis, from embryonic globins to adult globins, that encompasses nearly entirely the total globin ontogeny of this mammal. Synthesis of adult alpha globin is already detectable on day 7, whereas synthesis of the two adult beta globins does not appear until day 9. Synthesis of embryonic y globin stands in contrast to that of the other two embryonic globins (x and z), rising as they fall, a phenomenon reminiscent of the gamma globin of primates and certain ruminants. This physiologic primitive erythroid cell appears to be an unusually appropriate target for studies directed at globin ontogeny.
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PMID:The globin gene expression program in the hamster embryo. 333 31

Butyric acid, a naturally occurring fatty acid, has been shown to increase fetal hemoglobin in BFUe cultures, in primates, and in patients with beta chain hemoglobinopathies. The precise mechanism of gamma gene induction by butyrate is unknown. Butyrate may induce fetal hemoglobin production in vivo by reactivation of silenced gamma globin genes, by inhibiting the silencing of gamma genes, or by both mechanisms. We examined the effects of butyrate on gamma gene expression in transgenic mice carrying three types of constructs: microLCRA gamma mice, which continue to express the gamma gene in the adult stage of development at a level of one-third to one-fifth of the expression in the fetus; microLCRA gamma psi beta delta beta mice, which display correct developmental regulation of gamma and beta human globin genes and have low level gamma globin expression in the adult; and beta locus YAC mice, which display correct developmental regulation of epsilon, gamma, and beta globin genes and have a totally silenced gamma gene in the adult stage. Animals were treated with a continuous infusion of alpha-amino butyric acid (alpha-ABA) for 7 days. In microLCRA gamma mice alpha-ABA produced up to a 43-fold induction of gamma and 9-fold induction of mouse alpha globin genes. In contrast, butyrate did not induce gamma globin expression in the beta locus YAC mice. However, the gamma globin genes of beta locus YAC mice were activated after administration of 5-azacytidine (5-azaC), and the level of gamma globin expression was further increased by administration of alpha-ABA. These results suggest that butyrate cannot reactivate a totally silenced gamma gene and that induction of fetal hemoglobin by this compound may require the presence of preactivated gamma globin genes.
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PMID:alpha-Amino butyric acid cannot reactivate the silenced gamma gene of the beta locus YAC transgenic mouse. 752 73

Butyrate, a four-carbon fatty acid, and its two-carbon metabolic product, acetate, are inducers of gamma-globin synthesis. To test whether other short-chain fatty acids share this property, we first examined whether propionic acid, a three-carbon fatty acid that is not catabolized to acetate, induces gamma-globin expression. Sodium propionate increased the frequency of fetal hemoglobin containing erythroblasts and the gamma/gamma + beta mRNA ratios in adult erythroid cell cultures and F reticulocyte production in a nonanemic juvenile baboon. Short-chain fatty acids containing five (pentanoic), six (hexanoic), seven (heptanoic), eight (octanoic), and nine (nonanoic) carbons induced gamma-globin expression (as measured by increase in gamma-positive erythroblasts and gamma/gamma + beta mRNA ratios) in adult erythroid burst-forming unit cultures. There was a clear-cut relationship between the concentration of fatty acids in culture and the degree of induction of gamma-globin expression. Three-, four-, and five-carbon fatty acids were better inducers of gamma globin in culture as compared with six- to nine-carbon fatty acids. These results suggest that all short-chain fatty acids share the property of gamma-globin gene inducibility. The fact that valproic acid, a derivative of pentanoic acid, also induces gamma-globin expression suggests that short-chain fatty acid derivatives that are already approved for human use may possess the property of gamma-globin inducibility and may be of therapeutic relevance to the beta-chain hemoglobinopathies.
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PMID:Stimulation of fetal hemoglobin production by short chain fatty acids. 757 19

The inherited beta-hemoglobinopathies (sickle cell disease and beta thalassemia) are the result of a mutation in the adult (beta) globin gene. The fetal globin chain, encoded by the gamma globin genes, can substitute for the mutated or defective beta globin chain, but expression of the gamma globin gene is developmentally inactivated prior to birth. Re-inducing expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and the beta thalassemias. Stimulation of as little as 4-8% fetal globin synthesis in the bone marrow can produce > 20% fetal hemoglobin in the peripheral circulation, due to enhanced survival of red blood cells containing both sickle and fetal hemoglobin, compared to those containing sickle hemoglobin alone. Butyric acid and butyrate derivatives are generally safe compounds which induce fetal hemoglobin production by stimulating the promoter of the fetal globin genes. An initial trial with the parent compound, delivered as Arginine Butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that have been shown to ameliorate these conditions. Phase 1 trials of an oral butyrate derivative with a long plasma half-life have just begun. These agents now provide a specific new approach for ameliorating these classic molecular disorders and merit further investigation in larger patient populations.
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PMID:Butyrate-induced reactivation of the fetal globin genes: a molecular treatment for the beta-hemoglobinopathies. 768 3

Hemoglobin (Hb) F-Mauritius, a new A gamma chain variant, was identified from a dried blood spot collected from a heelprick during neonatal screening for the main hemoglobinopathies. This hemoglobin is the first gamma chain variant having a one residue deletion: it concerns alanine at position gamma 23. Hb F-Mauritius is therefore the counterpart of Hb Freiburg, an unstable variant of the beta chain in which the valine residue that occupies position beta 23 is deleted. The structural modification of Hb F-Mauritius was characterized by miniaturized protein chemistry methods, including sequence determination by mass spectrometry measurements. Hb Freiburg was used as a control in several experimental procedures. The hypothesis that a similar mechanism for deletion has occurred in Hb F-Mauritius and in Hb Freiburg is supported by the high percentage of homology observed between the beta and gamma globin genes. In addition, the first exon of the beta-globin has been recognized as a hotspot for deletion: several beta-thalassemic mutations, or abnormal Hbs, with deletions of short nucleotide sequences map in this region.
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PMID:Hb F-Mauritius [A gamma 23 (B5) Ala deleted]: evidence for an identical hotspot for deletions in the various beta-like genes. 855 53

VX-366 (isobutyramide) is an orally available branched chain amide that may offer an alternative to current treatments for beta-hemoglobinopathy. A phase I, double-blind, randomized, placebo-controlled study was conducted to investigate four single oral doses of VX-366 (1, 7, 14 or 28 grams or approximately 14, 100, 200 or 400 mg/kg) administered to four male volunteers each, with two other subjects in each group receiving a matching placebo. The total number of volunteers enrolled in this study was 24, with a mean age of 27 +/- 6.4 years. VX-366 was well tolerated at all dose levels studied, and peak plasma concentrations (Cmax) of 18.88 +/- 1.02 micrograms/mL (0.2 mmol/L), 171.13 +/- 32.13 micrograms/mL (2 mmol/L), 331.58 +/- 35.48 micrograms/mL (3.8 mmol/L), and 538.83 +/- 54.19 micrograms/mL (6 mmol/L) were achieved after the four respective doses. The half-life (t1/2) of VX-366 was more than 7 hours, and there was evidence of nonlinear pharmacokinetics. It is likely that nonrenal (metabolic) clearance plays a predominant role in elimination. Based on these data, VX-366 given as a single daily dose of 100 to 150 mg/kg should be well tolerated and can be expected to result in peak plasma levels in excess of 170 micrograms/mL (2 mmol/L) and in trough plasma levels in excess of 40 micrograms/mL (0.5 mmol/L). These plasma levels exceed the concentrations previously shown to stimulate gamma globin synthesis both in vitro and in baboons.
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PMID:Pharmacokinetics and safety of single oral doses of VX-366 (isobutyramide) in healthy volunteers. 884 44

Short-chain fatty acids, such as butyrate and propionate, induce fetal globin gene expression and are under clinical investigation in the beta-hemoglobinopathies. Limitations of the short-chain fatty acids as therapeutics include their rapid metabolism and a tendency to induce cell growth arrest if administered for prolonged periods. In studies described here, the cellular effects of other inducers of fetal globin, phenoxyacetic acid and derivatives of short-chain fatty acids and cinnamic acids, were investigated in the human erythroid cell line K562, the IL-3 dependent multi-lineage cell line (32D), and in mice and primates. Several test compounds supported 32D cell proliferation despite a 50-fold depletion of IL-3, which resulted in growth arrest and apoptotic death in control cells. The degree of proliferation induced by certain test compounds was similar to the degree of proliferation induced by Erythropoietin and G-CSF in the cells. Eight of ten compounds induced gamma globin mRNA in K562 cells. A 2.5 to 6-fold increase in reticulocytosis was observed in vivo in mice treated with two prototype compounds. Pharmacokinetic studies of three prototype compounds demonstrated millimolar plasma concentrations after single oral doses for many hours in primates. These findings identify orally bioavailable compounds which induce gamma globin gene expression and hematopoietic cell proliferation through an activity which partially abrogates requirements for IL-3. Such compounds provide potential for oral therapeutics which stimulate proliferation of hematopoietic cells of multiple lineages, as well as inducing fetal globin.
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PMID:Abrogation of IL-3 requirements and stimulation of hematopoietic cell proliferation in vitro and in vivo by carboxylic acids. 945 87

Quantitation of fetal hemoglobin (Hb F) and quantitation of it's gamma chain composition is important for the identification of different hemoglobinopathies. This is the first study done on the Jordanian newborns to test the hematological data and the gamma globin chain variants. A total of 52 randomly selected healthy Jordanian newborns were examined. The quantitation of the G gamma and A gamma chains combined with gene mapping using XmnI digestion, were used in the identification of one case of G gamma triplication among the studied samples. A family study of this case showed that adults carrying one copy of this G gamma triplication (13Kb XmnI fragment) had normal levels of HbF (< 1%) and high levels of G gamma (> 80%) while no homozygotes were detected. The remaining 51 newborns had normal frequency values of G gamma and A gamma chains. The frequency of the A gamma T chain among the 52 samples was 0.22. No abnormal alpha or beta chain variants were detected except for one case of HbS.
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PMID:Studies on fetal hemoglobin and gamma globin gene triplication in newborns in Jordan. 977 99


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