New Insights Into Pathophysiology of β-Thalassemia

Abstract

β-thalassemia is a disease caused by genetic mutations including a nucleotide change, small insertions or deletions in the β-globin gene, or in rare cases, gross deletions into the β-globin gene. These mutations affect globin-chain subunits within the hemoglobin tetramer what induces an imbalance in the α/β-globin chain ratio, with an excess of free α-globin chains that triggers the most important pathogenic events of the disease: ineffective erythropoiesis, chronic anemia/chronic hypoxia, compensatory hemopoietic expansion and iron overload. Based on advances in our knowledge of the pathophysiology of β-thalassemia, in recent years, emerging therapies and clinical trials are being conducted and are classified into three major categories based on the different approach features of the underlying pathophysiology: correction of the α/β-globin disregulation; improving iron overload and reverse ineffective erythropoiesis. However, pathways such as the dysregulation of transcriptional factors, activation of the inflammasome, or approach to mechanisms of bone mineral loss, remain unexplored for future therapeutic targets. In this review, we update the main pathophysiological pathways involved in β-thalassemia, focusing on the development of new therapies directed at new therapeutic targets.

Production and Characterization of K562 Cellular Clones Hyper-Expressing the Gene Encoding α-Globin: Preliminary Analysis of Biomarkers Associated with Autophagy

“…One of the most relevant pathophysiological parameters of β-thalassemia is the deep imbalance between the production of α-globin and that of β-globin, which is associated with the high accumulation rate of free α-globin in erythroid cells. The α-globin/β-globin imbalance is responsible of the most important and most clinically relevant pathogenic events associated with β-thalassemia, which are hemolysis, ineffective erythropoiesis, chronic anemia/chronic hypoxia, compensatory hemopoietic expansion and iron overload, as pointed out in several studies/reviews [ 1 , 2 , 3 , 4 , 5 , 6 ] and as recently reviewed by Villalobos et al [ 7 ].…”

“…The pathophysiology of β-thalassemia is also caused by an imbalance between α- and β-globin chains, with an excess of free α-globin chains, causing ineffective erythropoiesis and hemolysis [ 5 , 6 ]. Several studies sustain the concept that when β-thalassemia coexists with alterations of the number of α globin genes, the clinical phenotype of thalassemia could change from severe anemia, in the case of a triplication of the α globin genes, (αα/ααα) to mild anemia in the case of an α-globin gene deletion [ 5 , 6 , 7 , 8 ]. Therefore, the reduction of free α-globin chains has a clear clinical impact, as suggested by a large number of studies [ 9 , 10 , 11 , 12 ] demonstrating that when α-thalassemia is co-inherited with β-thalassemia, the excess free α-globin chains is reduced significantly, ameliorating the clinical severity.…”

β-Thalassemia and Diabetes Mellitus: Current State and Future Directions

“…The disorder is highly prevalent in Southern Europe, the Middle East, Southeast Asia, and the Indian subcontinent [6,7]. It is also common in some Northern and Central European countries and Latin America [8]. Although thalassemia comes in different genetic forms and variable degrees of severity, β-thalassemia major is the most prevalent among the severe variants of thalassemia.…”

“…Thalassemia originates due to the reduction or absence of globin chain production, resulting in defective hemoglobin synthesis. This defect causes uncontrolled destruction of erythrocytes (red blood cells), leading to severe chronic anemia in which patients require lifelong blood transfusion and Review β-Thalassemia and Diabetes Mellitus: Current State and Future Directions Review iron chelating therapy [8]. Clinical manifestations of thalassemia vary depending on the type and severity of the disease, and it ranges from no clinical manifestations to transfusion-dependent to fatal [10].…”

Precise modelling and correction of a spectrum of β-thalassemic mutations in human erythroid cells by base editors

“…β-thalassemia represent one of the most common inherited monogenic disorders worldwide caused due to a spectrum of mutations in the β-globin gene, which results in a quantitative decrease in the production of functional β-globin chain or generation of structural hemoglobin (Hb) variants(1). The reduction or absence of β-globin chain synthesis caused due to mutations in the β-globin gene creates an imbalance in the α/β globin chain ratio leading to ineffective erythropoiesis(2). The degree of an imbalance created correlates with the severity of the phenotype, based on which β-thalassemia is categorised as β-thalassemia major (β 0 / β 0 - homozygous or as compound heterozygous with Hb structural variants), β-thalassemia intermedia (β 0 / β + - heterozygous) and β-thalassemia minor (β/ β +/0 - heterozygous)(3).…”