New therapeutic targets in transfusion-dependent and -independent thalassemia

Research output: Contribution to journalArticle

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Abstract

β-Thalassemias are characterized by reduced production of β-globin chain, resulting in a/b-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 b-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.

Original languageEnglish
Pages (from-to)278-283
Number of pages6
JournalHematology
Volume2017
Issue number1
DOIs
Publication statusPublished - Dec 8 2017

Fingerprint

Thalassemia
Erythropoiesis
Iron
Hemoglobin E
Therapeutics
Iron Overload
Globins
Graft vs Host Disease
Hematopoietic Stem Cells
Activin Receptors
Hemolytic Anemia
Intestinal Absorption
Heme
Epigenomics
Genetic Therapy
Anemia
Tissue Donors
Clinical Trials
Ligands
Transplants

ASJC Scopus subject areas

  • Hematology

Cite this

New therapeutic targets in transfusion-dependent and -independent thalassemia. / Cappellini, M. Domenica; Motta, Irene.

In: Hematology, Vol. 2017, No. 1, 08.12.2017, p. 278-283.

Research output: Contribution to journalArticle

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