A mouse model for beta 0-thalassemia.

Yang, Baoli; Kirby, Suzanne L.; Lewis, Jada; Detloff, Peter J.; Maeda, Nobuyo; Smithies, Oliver

doi:10.1073/pnas.92.25.11608

Cited by 230 publications

(214 citation statements)

References 20 publications

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“…The availability of natural 1,2 and knock-out mouse models 3,4 for this pathology is helpful in devising therapeutic approaches, especially in reducing the amount of membrane-bound ␣ globin chain and the ␣/non-␣ globin chain imbalance as well as increasing fetal or similar hemoglobin. 5, 6 The natural mouse ␤-thalassemic model (Hbb thal 1) used in this present study is a consequence of the deletion of the ␤ major globin gene 2 .…”

Section: Introductionmentioning

confidence: 99%

Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

et al. 1999

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Section: Introductionmentioning

confidence: 99%

Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

et al. 1999

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“…Ahsp Ϫ/Ϫ mice were generated as described previously (10). ␤-Thalassemic (␤-globin Th3/ϩ ) mice were kindly provided by Oliver Smithies (University of North Carolina, Chapel Hill, NC) (48). The Ahsp allele is genetically linked to the ␤-globin (Hbb) locus (11); Ahsp/␤-globin Th3/ϩ double mutant mice were generated as described previously (11).…”

Section: Rates Of ␣ Subunit Binding and Release From Promentioning

confidence: 99%

Insights into Hemoglobin Assembly through in Vivo Mutagenesis of α-Hemoglobin Stabilizing Protein

Khandros

Mollan

et al. 2012

Journal of Biological Chemistry

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Background:The ␣-hemoglobin-stabilizing protein (AHSP) facilitates hemoglobin assembly. Results: AHSP mutations that enhance binding affinity for ␣-globin or slow its rate of autooxidation in vitro do not affect normal or stressed erythropoiesis in mice. Conclusion: AHSP exhibits robust molecular chaperone activity in vivo even when its biochemical interactions with reduced ␣-globin are perturbed. Significance: Our findings support new models for AHSP activities in vivo.

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“…14 We therefore attempted to adoptively transfer the hematologic deficit to adult mice by transplanting FLCs harvested from screened ED 14.5 embryos ( Figure 1A). Congenic C57BL/6 recipient mice were irradiated (12 Gy) before intravenous infusion of 2 ϫ 10 6 FLCs.…”

Section: Establishment Of An Adult Mouse Model Of ␤-Thalassemia Majormentioning

confidence: 99%

A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer

Rivella

May

Chadburn

et al. 2003

Blood

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Patients affected by ␤-thalassemia major require lifelong transfusions because of insufficient or absent production of the ␤ chain of hemoglobin (Hb). A minority of patients are cured by allogeneic bone marrow transplantation. In the most severe of the hitherto available mouse models of ␤-thalassemia, a model for human ␤-thalassemia intermedia, we previously demonstrated that globin gene transfer in bone marrow cells is curative, stably raising Hb levels from 8.0-8.5 to 11.0-12.0 g/dL in long-term chimeras. To fully assess the therapeutic potential of gene therapy in the context of a lethal anemia, we now have created an adult model of ␤ 0 -thalassemia major. In this novel model, mice engrafted with ␤-globin-null (Hbb th3/th3 ) fetal liver cells succumb to ineffective erythropoiesis within 60 days. These mice rapidly develop severe anemia (2-4 g/dL), massive splenomegaly, extramedullary hematopoiesis (EMH), and hepatic iron overload. Remarkably, most mice (11 of 13) treated by lentivirus-mediated globin gene transfer were rescued. Long-term chimeras with an average 1.0-2. IntroductionThe ␤-thalassemias are caused by more than 200 mutations that lead to decreased or absent production of the ␤ chain of hemoglobin (Hb). 1-3 Most of the mutations are point mutations in the ␤-globin gene that either decrease the level of transcription or mRNA stability or lead to nonfunctional mRNA, as is the case in nonsense and frameshift mutations. Other mutations include deletions in the ␤-globin gene, as well as rare deletions located distally to the ␤-globin gene itself. 1,3,4 There is a large spectrum in the severity of the disease found in homozygotes and compound heterozygotes. Patients affected by ␤-thalassemia intermedia do not require chronic transfusion therapy in the first years of life, but they often worsen over time, eventually developing hypersplenism, osteopenia, extramedullary hematopoiesis (EMH), and iron overload. Some patients eventually require splenectomy and blood transfusions. In patients with ␤-thalassemia major, or Cooley anemia, the absent or extremely reduced production of the ␤ chain of Hb causes severe ineffective erythropoiesis, massive erythroid hyperplasia in the bone marrow and extramedullary sites, and hemolysis. The ensuing iron overload can lead to endocrine deficiencies, cirrhosis, and cardiac failure. In the absence of lifelong transfusions, the disease is lethal. 5 Current disease management consists of prenatal diagnosis, transfusion therapy, or allogeneic bone marrow transplantation. 1,3,4 Only the latter is curative, but this option is limited to a minority of patients for whom a histocompatible donor can be identified.New approaches aimed at ameliorating the condition of patients with severe ␤-thalassemia are greatly needed. Genetic approaches based on the transfer of a regulated human ␤-globin gene in autologous hematopoietic stem cells (HSCs) represent an attractive potential treatment. 6 Their implementation has been hampered by the difficulty of appropriately regulating expression o...

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A mouse model for beta 0-thalassemia.

Abstract: We have used a "plug and socket" targeting technique to generate a mouse model of 130-thalassemia

Cited by 230 publications

References 20 publications

Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

Improvement of mouse β-thalassemia upon erythropoietin delivery by encapsulated myoblasts

Insights into Hemoglobin Assembly through in Vivo Mutagenesis of α-Hemoglobin Stabilizing Protein

A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human β-globin gene transfer

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