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New therapeutic targets in transfusion-dependent and -independent thalassemia - PubMed

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New therapeutic targets in transfusion-dependent and -independent thalassemia

M Domenica Cappellini et al. Hematology Am Soc Hematol Educ Program. 2017.

Abstract

β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.

© 2016 by The American Society of Hematology. All rights reserved.

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Conflict of interest statement

Conflict-of-interest disclosure: M.D.C. is on the Board of Directors or an advisory committee for Celgene and Sanofi Genzyme. I.M. declares no competing financial interests.

Figures

Figure 1.
Figure 1.

New therapeutic targets in β-thalassemias: (A,D) impaired α:β-globin ratio, (B) ineffective erythropoiesis, and (C) iron metabolism and hemolysis. TMPRSS6, transmembrane protease serine 6.

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References

    1. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010;115(22):4331-4336. - PMC - PubMed
    1. Weatherall DJ. Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet. 2001;2(4):245-255. - PubMed
    1. Tavazzi D, Duca L, Graziadei G, Comino A, Fiorelli G, Cappellini MD. Membrane-bound iron contributes to oxidative damage of beta-thalassaemia intermedia erythrocytes. Br J Haematol. 2001;112(1):48-50. - PubMed
    1. Gardenghi S, Marongiu MF, Ramos P, et al. . Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. 2007;109(11):5027-5035. - PMC - PubMed
    1. Cappellini MD, Cohen A, Porter J, et al. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT). 3rd ed. Nicosia, Cyprus: Thalassaemia International Federation; 2014. - PubMed

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