scholarly journals Improvement of mouse beta-thalassemia by recombinant human erythropoietin

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1596-1602 ◽  
Author(s):  
K Leroy-Viard ◽  
P Rouyer-Fessard ◽  
Y Beuzard
Keyword(s):  
Recombinant Human Erythropoietin ◽  
Cell Mass ◽  
Thiol Group ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Trichloracetic Acid ◽  
Human Erythropoietin ◽  
Alpha Globin ◽  
Chain Imbalance ◽  
Chain Synthesis

Homozygous beta thalassemic mice received 50 U (1,660 U/kg) of recombinant human erythropoietin (rhEpo) 5 days a week for 2 weeks. Hemoglobin increased from 9.2 +/- 0.6 g/dL to 10.5 +/- 0.4 g/dL (P = .002) and hematocrit increased from 29.2% +/- 0.9% to 34.1% +/- 1.9% (P = .0014). The beta minor/alpha globin chain synthesis ratio increased slightly but significantly between day -4 (0.75 +/- 0.07) and day 4 (0.81 +/- 0.04) (P = .01) and reached a minimum ratio (0.67 +/- 0.03) on day 15 (P = .001), being parallel to reticulocyte counts and to the incorporated trichloracetic acid (TCA)-insoluble radioactivity, therefore parallel to the erythropoietic output in thalassemic mice, as in normal mice. Erythrocyte defects were improved in beta thalassemic mice treated by rhEpo: membrane-associated alpha globin was significantly decreased (P less than .01), thiol group reactivity of ankyrin was significantly improved (P less than .05), spectrin alterations were reduced, and deformability of mouse thalassemic red blood cells was normalized. These results provide experimental criteria for modulating globin chain imbalance necessary for the therapy of human beta thalassemia intermedia, and suggest that rhEpo might be of interest to improve the red blood cell mass and reduce erythrocyte alterations in this disease.

scholarly journals Improvement of mouse beta-thalassemia by recombinant human erythropoietin

Blood ◽  
1991 ◽  
Vol 78 (6) ◽  
pp. 1596-1602 ◽  
Author(s):  
K Leroy-Viard ◽  
P Rouyer-Fessard ◽  
Y Beuzard
Keyword(s):  
Recombinant Human Erythropoietin ◽  
Cell Mass ◽  
Thiol Group ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Trichloracetic Acid ◽  
Human Erythropoietin ◽  
Alpha Globin ◽  
Chain Imbalance ◽  
Chain Synthesis

Abstract Homozygous beta thalassemic mice received 50 U (1,660 U/kg) of recombinant human erythropoietin (rhEpo) 5 days a week for 2 weeks. Hemoglobin increased from 9.2 +/- 0.6 g/dL to 10.5 +/- 0.4 g/dL (P = .002) and hematocrit increased from 29.2% +/- 0.9% to 34.1% +/- 1.9% (P = .0014). The beta minor/alpha globin chain synthesis ratio increased slightly but significantly between day -4 (0.75 +/- 0.07) and day 4 (0.81 +/- 0.04) (P = .01) and reached a minimum ratio (0.67 +/- 0.03) on day 15 (P = .001), being parallel to reticulocyte counts and to the incorporated trichloracetic acid (TCA)-insoluble radioactivity, therefore parallel to the erythropoietic output in thalassemic mice, as in normal mice. Erythrocyte defects were improved in beta thalassemic mice treated by rhEpo: membrane-associated alpha globin was significantly decreased (P less than .01), thiol group reactivity of ankyrin was significantly improved (P less than .05), spectrin alterations were reduced, and deformability of mouse thalassemic red blood cells was normalized. These results provide experimental criteria for modulating globin chain imbalance necessary for the therapy of human beta thalassemia intermedia, and suggest that rhEpo might be of interest to improve the red blood cell mass and reduce erythrocyte alterations in this disease.

scholarly journals A family with segregating triplicated alpha globin loci and beta thalassemia

Blood ◽  
1983 ◽  
Vol 62 (5) ◽  
pp. 1035-1040 ◽  
Author(s):  
R Galanello ◽  
R Ruggeri ◽  
E Paglietti ◽  
M Addis ◽  
MA Melis ◽  
...  
Keyword(s):  
Globin Gene ◽  
Phenotypic Expression ◽  
Beta Thalassemia ◽  
Heterozygous State ◽  
Globin Chain ◽  
Homozygous State ◽  
Alpha Globin ◽  
Triple Alpha ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract In this article we report a Sardinian family, in which a beta- thalassemia gene and a triple alpha-globin loci, counterpart of the rightward deletion type alpha-thalassemia-2, were segregating. The analysis of the genotype-phenotype correlations in the different family members allowed us to give an outline of the manifestations associated with different genotype combinations. The heterozygote for the triple alpha-loci showed no consistent abnormal clinical or hematologic characteristics and presented balanced alpha/beta-globin chain synthesis. In the homozygous state for this lesion, the only phenotypic expression was a slightly imbalanced globin chain synthesis. The combination of heterozygous beta-thalassemia with the heterozygous state for the triple alpha-globin loci produced no clinical manifestations and showed a hematologic phenotype indistinguishable from that of heterozygous beta-thalassemia. On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.

scholarly journals A family with segregating triplicated alpha globin loci and beta thalassemia

Blood ◽  
1983 ◽  
Vol 62 (5) ◽  
pp. 1035-1040
Author(s):  
R Galanello ◽  
R Ruggeri ◽  
E Paglietti ◽  
M Addis ◽  
MA Melis ◽  
...  
Keyword(s):  
Globin Gene ◽  
Phenotypic Expression ◽  
Beta Thalassemia ◽  
Heterozygous State ◽  
Globin Chain ◽  
Homozygous State ◽  
Alpha Globin ◽  
Triple Alpha ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

In this article we report a Sardinian family, in which a beta- thalassemia gene and a triple alpha-globin loci, counterpart of the rightward deletion type alpha-thalassemia-2, were segregating. The analysis of the genotype-phenotype correlations in the different family members allowed us to give an outline of the manifestations associated with different genotype combinations. The heterozygote for the triple alpha-loci showed no consistent abnormal clinical or hematologic characteristics and presented balanced alpha/beta-globin chain synthesis. In the homozygous state for this lesion, the only phenotypic expression was a slightly imbalanced globin chain synthesis. The combination of heterozygous beta-thalassemia with the heterozygous state for the triple alpha-globin loci produced no clinical manifestations and showed a hematologic phenotype indistinguishable from that of heterozygous beta-thalassemia. On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.

scholarly journals Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta- thalassemia

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 928-933 ◽  
Author(s):  
JL Villeval ◽  
P Rouyer-Fessard ◽  
N Blumenfeld ◽  
A Henri ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Bone Marrow Cells ◽  
Elevated Serum ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Alpha Globin ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta- thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta- thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.

scholarly journals Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta- thalassemia

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 928-933 ◽  
Author(s):  
JL Villeval ◽  
P Rouyer-Fessard ◽  
N Blumenfeld ◽  
A Henri ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Bone Marrow Cells ◽  
Elevated Serum ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Alpha Globin ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta- thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta- thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.

scholarly journals Changes in the kinetics and biopotency of luteinizing hormone in hemodialyzed men during treatment with recombinant human erythropoietin.

1994 ◽  
Vol 5 (5) ◽  
pp. 1208-1215
Author(s):  
F Schaefer ◽  
B van Kaick ◽  
J D Veldhuis ◽  
G Stein ◽  
K Schärer ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Half Life ◽  
Recombinant Human Erythropoietin ◽  
Cell Mass ◽  
Elimination Kinetics ◽  
Deconvolution Analysis ◽  
Human Erythropoietin ◽  
Change In Mean ◽  
Plasma Half Life

To investigate the effect of recombinant human erythropoietin (rh-EPO) on the hypothalamo-pituitary-gonadal axis in end-stage renal failure, plasma luteinizing hormone (LH) concentration release was assessed by frequent blood sampling (every 10 min), both during an 8-h baseline period and after stimulation with an iv bolus of gonadotropin-releasing hormone (GnRH). Seven adult hemodialyzed men were studied before and after partial correction of anemia by rh-EPO treatment. LH was determined by an in vitro Leydig cell bioassay (bio-LH) and a highly sensitive immunoradiometric assay. Pulsatile bio-LH secretion and clearance characteristics were assessed by multiple-parameter deconvolution analysis. Although the rh-EPO treatment did not lead to a change in average concentrations of plasma bio-LH, the mass of hormone released per secretory burst more than doubled, and the estimated bio-LH production rate increased from 8.8 +/- 2.3 to 15.6 +/- 5.2 IU/L per hour (P = 0.05). The lack of change in mean plasma bio-LH is explained by a simultaneous decrease in plasma half-life from 106 +/- 27 to 67 +/- 19 min (P < 0.02). The decrease in the plasma half-life of bio-LH was closely associated with the rise in hematocrit, suggesting an effect of the increased red blood cell mass on LH distribution space and elimination kinetics. As a consequence of the changes in hormone kinetics, the incremental amplitudes of the plasma concentration pulses of bio-LH increased from 112 to 121% of nadir levels (P < 0.05), resulting in a more distinctly pulsatile pattern of hormone signals.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Asynchronous globin chain synthesis in rabbit reticulocyte lystates induced by hemin-controlled repressor

Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 653-658 ◽  
Author(s):  
RS Franco ◽  
JW Hogg ◽  
OJ Martelo
Keyword(s):  
Globin Chain ◽  
Free System ◽  
Globin Chains ◽  
Reticulocyte Lysate ◽  
Chain Imbalance ◽  
Globin Synthesis ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract To define further the role of hemin-controlled repressor (HCR) in globin synthesis, we studied its effect on the synthesis of individual globin chains in a rabbit reticulocyte lysate cell-free system. In the presence of HCR there was a marked globin chain imbalance, resulting in a lowered alpha/beta ratio. These findings in vitro may have relevance to certain clinical heme deficiency states in which a similar globin chain imbalance has been observed.

scholarly journals Globin-chain specificity of oxidation-induced changes in red blood cell membrane properties

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1586-1592 ◽  
Author(s):  
SL Schrier ◽  
N Mohandas
Keyword(s):  
Membrane Damage ◽  
Membrane Skeleton ◽  
Material Behavior ◽  
Membrane Properties ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Globin Chain ◽  
Globin Chains ◽  
Alpha Globin

Abstract We have previously shown that excess unpaired alpha- and beta-globin chains in severe alpha- and beta-thalassemia interacting with the membrane skeleton induce different changes in membrane properties of red blood cells (RBCs) in these two phenotypes. We suggest that these differences in membrane material behavior may reflect the specificity of the membrane damage induced by alpha- and beta-globin chains. To further explore this hypothesis, we sought in vitro models that induce similar membrane alterations in normal RBCs. We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia. Methylhydrazine, in contrast, induced selective association of oxidized beta-globin chains with the membrane skeleton and produced rigid but hyperstable membranes, features that mimicked those of RBCs in severe alpha- thalassemia. These findings suggest that consequences of oxidation induced by globin chains are quite specific in that those agents that cause alpha-globin chain accumulation at the membrane produce rigid but mechanically unstable membranes, whereas membrane accumulation of beta- globin chains results in rigid but mechanically stable membranes. These in vitro experiments lend further support to the hypothesis that membrane-associated alpha- and beta-chains induce oxidative damage to highly specific different skeletal components and that the specificity of this skeletal damage accounts for the differences in material membrane properties of these oxidatively attacked RBCs and perhaps of alpha- and beta-thalassemic RBCs as well.

scholarly journals Globin Chain Synthesis in the Marrow and Reticulocytes of Beta Thalassemia, Hemoglobin H Disease, and Beta Delta Thalassemia

Blood ◽  
1972 ◽  
Vol 40 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Mordechai Shchory ◽  
Bracha Ramot
Keyword(s):  
Bone Marrow ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Globin Chain ◽  
Thalassemia Intermedia ◽  
Thalassemia Minor ◽  
Order Of Magnitude ◽  
Hb H Disease ◽  
Chain Synthesis ◽  
Globin Chain Synthesis

Abstract α, β, and γ globin chain synthesis in bone marrow and peripheral blood reticulocytes were studied in two patients with thalassemia major, two with thalassemia intermedia, one with thalassemia minor, one with Hb H disease, and one with homozygous βδ-thalassemia. Nine nonthalassemic patients served as controls. In thalassemia major, a marked imbalance of α- to β-chain synthesis was found in the bone marrow as well as in reticulocytes. The imbalance, however, was slightly more evident in the latter. In the patients with thalassemia intermedia and minor the α- to β-globin chain ratios in the reticulocytes were of the same order of magnitude, despite the marked clinical differences between thalassemia intermedia and minor. A balanced synthesis was found in the bone marrow of the patient with thalassemia minor. The bone marrow globin synthesis in thalassemia intermedia was not studied. Contrary to that in Hb H disease and βδ-thalassemia, the imbalance was more apparent in the bone marrow. In the latter, no evidence for imbalance was detected in the reticulocytes. These results point out the need for further studies on globin chain synthesis in the bone marrow and reticulocytes of patients With the various thalassemia syndromes and the effect of the free globin chain pool on those results.

scholarly journals Delta +-thalassemia in Sardinia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 341-345 ◽  
Author(s):  
M Pirastu ◽  
R Galanello ◽  
MA Melis ◽  
C Brancati ◽  
A Tagarelli ◽  
...  
Keyword(s):  
Restriction Endonuclease ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Globin Chain ◽  
New Type ◽  
Polymorphic Restriction ◽  
Chain Synthesis ◽  
Double Heterozygosity ◽  
Globin Chain Synthesis

Abstract We have defined a new type of delta-thalassemia in which beta-globin chain synthesis is incompletely suppressed. Homozygotes have unusually low HbA2 levels, and double heterozygosity for this delta-thalassemia gene and beta-thalassemia normalizes the HbA2 level. The delta- thalassemia occurs on a chromosome that is identifiable using polymorphic restriction endonuclease sites. We call this condition delta +-thalassemia, to distinguish it from the previously described delta 0-thalassemia syndromes in which no delta-globin chain synthesis occurs.

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