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Frederic Galacteros - One of the best experts on this subject based on the ideXlab platform.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert α131 h14 ser pro and hb caen α132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:: Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert alpha 131 h14 ser pro and hb caen alpha 132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
Mark D. Fleming - One of the best experts on this subject based on the ideXlab platform.
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RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-thalassemia intermedia.
American journal of hematology, 2018Co-Authors: Paul J. Schmidt, Kaifeng Liu, Gary A. Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia Hettinger, James Butler, Mark D. FlemingAbstract:Diminished β-Globin Synthesis in β-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β-thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of Tmprss6 in splenectomized β-thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β-thalassemia patients.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia
American Journal of Hematology, 2015Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-Globin Synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia short title tmprss6 sirna and deferiprone combination therapy in mur
2014Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-Globin Synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAitherapeutic downregulating Tmprss6, β-thalassemic Hbb animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Page 2 of 13 John Wiley & Sons American Journal of Hematology This article is protected by copyright. All rights reserved.
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an rnai therapeutic targeting tmprss6 decreases iron overload in hfe mice and ameliorates anemia and iron overload in murine β thalassemia intermedia
Blood, 2013Co-Authors: Paul J. Schmidt, Tim Racie, Julia Hettinger, Anoop K. Sendamarai, Ivanka Toudjarska, David Bumcrot, Stuart Milstein, Brian Bettencourt, Mark D. FlemingAbstract:Mutations in HFE lead to hereditary hemochromatosis (HH) because of inappropriately high iron uptake from the diet resulting from decreased hepatic expression of the iron-regulatory hormone hepcidin. β-thalassemia is a congenital anemia caused by partial or complete loss of β-Globin Synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload. Tmprss6 is postulated to regulate hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the hepatocyte surface. On this basis, we hypothesized that treatment of mouse models of HH (Hfe−/−) and β-thalassemia intermedia (Hbbth3/+) with Tmprss6 siRNA formulated in lipid nanoparticles (LNPs) that are preferentially taken up by the liver would increase hepcidin expression and lessen the iron loading in both models. In the present study, we demonstrate that LNP-Tmprss6 siRNA treatment of Hfe−/− and Hbbth3/+ mice induces hepcidin and diminishes tissue and serum iron levels. Furthermore, LNP-Tmprss6 siRNA treatment of Hbbth3/+ mice substantially improved the anemia by altering RBC survival and ineffective erythropoiesis. Our results indicate that pharmacologic manipulation of Tmprss6 with RNAi therapeutics isa practical approach to treating iron overload diseases associated with diminished hepcidin expression and may have efficacy in modifying disease-associated morbidities of β-thalassemia intermedia.
Dominique Labie - One of the best experts on this subject based on the ideXlab platform.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert α131 h14 ser pro and hb caen α132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:: Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert alpha 131 h14 ser pro and hb caen alpha 132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
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increased protein binding to a 530 mutation of the human beta Globin gene associated with decreased beta Globin Synthesis
American Journal of Hematology, 1991Co-Authors: Patricia E Berg, Dominique Labie, Moshe Mittelman, Jacques Elion, Alan N SchechterAbstract:Although some cases of the syndrome of hereditary persistence of fetal hemoGlobin (HPFH) have been correlated with mutations causing a change in the binding of trans-acting factors to DNA sequences flanking the gamma-Globin gene, this mechanism has not been described in beta-thalassemias upstream of the canonical promoter of the beta-Globin gene. In this report we describe such a change in binding of a protein that may explain a silent carrier phenotype of beta-thalassemia. We have previously demonstrated the binding of a protein (BP1) derived from a nuclear extract of human K562 cells to DNA 5' to the human beta-Globin gene in a region having a negative regulatory function. The binding of BP1 in this region can be detected by DNAse I footprinting and by gel mobility shift analysis. We have now compared binding of BP1 to the normal sequence and a mutated sequence (+ATA/-T at -530 bp from the cap site) from the silent carrier of beta-thalassemia. Using mobility shift assays we show that BP1 binds about nine times more strongly to the mutated sequence than the normal sequence. These results suggest the possibility that the decreased expression of the beta-Globin gene exhibited by the carrier may be due, at least in part, to tighter binding of a protein which functions as a negative control element or repressor.
Henri Wajcman - One of the best experts on this subject based on the ideXlab platform.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert α131 h14 ser pro and hb caen α132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:: Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
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unstable alpha chain hemoGlobin variants with factitious beta thalassemia biosynthetic ratio hb questembert alpha 131 h14 ser pro and hb caen alpha 132 h15 val gly
American Journal of Hematology, 1993Co-Authors: Henri Wajcman, Corinne Vasseur, Y Blouquit, J Rosa, Dominique Labie, A Najman, O Reman, M Leporrier, Frederic GalacterosAbstract:Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoGlobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same Globin bioSynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced Globin Synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoGlobin, thus leading to an apparent suppression of beta-chain Synthesis, or 3) to a modified stability of the abnormal alpha-Globin mRNA.
Paul J. Schmidt - One of the best experts on this subject based on the ideXlab platform.
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RNAi-mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β-thalassemia intermedia.
American journal of hematology, 2018Co-Authors: Paul J. Schmidt, Kaifeng Liu, Gary A. Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia Hettinger, James Butler, Mark D. FlemingAbstract:Diminished β-Globin Synthesis in β-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β-thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of Tmprss6 in splenectomized β-thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β-thalassemia patients.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia
American Journal of Hematology, 2015Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-Globin Synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAi-therapeutic downregulating Tmprss6, β-thalassemic Hbbth3/+ animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbbth3/+ animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Am. J. Hematol. 90:310–313, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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combination therapy with a tmprss6 rnai therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β thalassemia intermedia short title tmprss6 sirna and deferiprone combination therapy in mur
2014Co-Authors: Paul J. Schmidt, Kevin Fitzgerald, Tim Racie, James Butler, Mark Westerman, Mark D. FlemingAbstract:β-thalassemias result from diminished β-Globin Synthesis and are associated with ineffective erythropoiesis and secondary iron overload caused by inappropriately low levels of the iron regulatory hormone hepcidin. The serine protease TMPRSS6 attenuates hepcidin production in response to iron stores. Hepcidin induction reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To further interrogate the efficacy of an RNAitherapeutic downregulating Tmprss6, β-thalassemic Hbb animals on an iron replete, an iron deficient, or an iron replete diet also containing the iron chelator deferiprone were treated with Tmprss6 siRNA. We demonstrate that the total body iron burden is markedly improved in Hbb animals treated with siRNA and chelated with oral deferiprone, representing a significant improvement compared to either compound alone. These data indicate that siRNA suppression of Tmprss6, in conjunction with oral iron chelation therapy, may prove superior for treatment of anemia and secondary iron loading seen in β-thalassemia intermedia. Page 2 of 13 John Wiley & Sons American Journal of Hematology This article is protected by copyright. All rights reserved.
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an rnai therapeutic targeting tmprss6 decreases iron overload in hfe mice and ameliorates anemia and iron overload in murine β thalassemia intermedia
Blood, 2013Co-Authors: Paul J. Schmidt, Tim Racie, Julia Hettinger, Anoop K. Sendamarai, Ivanka Toudjarska, David Bumcrot, Stuart Milstein, Brian Bettencourt, Mark D. FlemingAbstract:Mutations in HFE lead to hereditary hemochromatosis (HH) because of inappropriately high iron uptake from the diet resulting from decreased hepatic expression of the iron-regulatory hormone hepcidin. β-thalassemia is a congenital anemia caused by partial or complete loss of β-Globin Synthesis causing ineffective erythropoiesis, anemia, decreased hepcidin production, and secondary iron overload. Tmprss6 is postulated to regulate hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the hepatocyte surface. On this basis, we hypothesized that treatment of mouse models of HH (Hfe−/−) and β-thalassemia intermedia (Hbbth3/+) with Tmprss6 siRNA formulated in lipid nanoparticles (LNPs) that are preferentially taken up by the liver would increase hepcidin expression and lessen the iron loading in both models. In the present study, we demonstrate that LNP-Tmprss6 siRNA treatment of Hfe−/− and Hbbth3/+ mice induces hepcidin and diminishes tissue and serum iron levels. Furthermore, LNP-Tmprss6 siRNA treatment of Hbbth3/+ mice substantially improved the anemia by altering RBC survival and ineffective erythropoiesis. Our results indicate that pharmacologic manipulation of Tmprss6 with RNAi therapeutics isa practical approach to treating iron overload diseases associated with diminished hepcidin expression and may have efficacy in modifying disease-associated morbidities of β-thalassemia intermedia.