α-Globin as a molecular target in the treatment of β-thalassemia

Abstract

The thalassemias, together with sickle cell anemia and its variants, are the world’s most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

Thalassaemia: In a quest towards an ultimate cure

“…We published these findings in a recent review article in 'Blood' where we concluded that a reduction of α-globin levels by 25%-50% in patients with β-thalassaemia should reduce or in fact eliminate the need of blood transfusion and could lead to a possible 'cure' 14 . However, to use this phenomenon as a therapeutic tool, we need to selectively reduce the production of α-globin without affecting the production of β-globin.…”

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

“…3 Several genetic modulators [4][5][6][7][8] and cis-regulatory elements [8][9][10][11][12] involved in the regulation of human fetal hemoglobin (HbF), and concomitant a-thalassemia (MIM 604131) have been identified as ameliorators of b-thalassemia. 13 These modifiers included HBG2: À158C>T (NC_ 000011.9: g.5276169G>A, rs7482144, or XmnI polymorphism) in the b-globin cluster identified to be linked to HBG1: þ25G>A polymorphism (NC_000011.9: g.5271063C>T or rs368698783), 12,14 and the master genes involved in the regulation of fetal-to-adult hemoglobin (Hb) switching, including B cell CLL/lymphoma 11A (BCL11A [MIM 606557]), 5,8,15 Kruppel-like factor 1 (KLF1 [MIM 600599]), 6,15 and MYB (MIM 189990). 7,15 Identifying regulators of Hb switching including these genetic variants could provide promising predictors of b-thalassemia severity and therapeutic targets for re-activating HbF production.…”

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

“…With the unraveling of complex genetic and environmental factors modulating clinical severity, new potential therapeutic approaches are under development [e.g., (65,147)]: gene switching (19) that includes HbF induction by hydroxyurea; stem cell transplants; gene therapy; pharmacological targeting of defective erythropoiesis; targeting free a-chains and with a-Hb chaperones; and countering the vasculature depletion of NO from chronic hemolysis (18,19,36,102,111,133,179,189).…”