The β-thalassemia syndromes are heterogeneous autosomal recessive hereditary disorders, caused by alterations in the HBB gene and characterized by absent or reduced β-globin chain synthesis. The β-thalassemia phenotypes are variable, ranging from severe, transfusion-dependent thalassemia major to mild, asymptomatic thalassemia trait. This interpatient clinical variability has swayed researchers toward identifying genetic modifiers for these disorders. Primary modifiers refer to type of alterations affecting β-globin gene. Secondary modifiers include variations in genes affecting α/β-globin chain equilibrium, such as genes involved in the γ-globin gene expression and genes affecting the amount and stability of α-globin chains. Tertiary modifiers are gene variations affecting the phenotype with regard to the complications caused by β-thalassemia syndromes. A role of secondary genetic modifiers in ameliorating the clinical phenotype has been observed. Secondary genetic modifiers are the most common targets for modern therapy and could be located within α- and γ-globin genes or outside globin gene cluster. The most potent secondary modifier genes are γ-globin genes. Production of fetal hemoglobin (HbF) trough adulthood ameliorates the severity of β-thalassemia phenotype. Large family and genome-wide association studies have shown that regions outside of the β-globin gene cluster are also implicated in γ-globin gene expression regulation. HBS1-MYB intragenic region and BCL11A gene have been particularly studied. Variants within these loci, along with γ-globin gene variants, account for approximately 50% of the HbF level variation, suggesting that additional factors are involved (transcription regulators (KLF1), regulators of α-globin chain stability (AHSP), epigenetic regulators (FoP)). Until recently a definitive cure for β-thalassemia could be achieved with bone marrow transplantation. However, it is available for less than 30% of the patients and bears a significant risk of morbidity and mortality. Alternative strategies, such as gene therapy and development of induced pluripotent stem cells (iPSCs) have been explored. The targets for gene therapy are hematopoietic stem cells, which are harvested from patient bone marrow or peripheral blood, purified by immunoselection, transduced by “therapeutic gene” aimed at correcting the effect of defective β-globin gene, and returned to the patient. Various types of vectors have been considered for gene transfer, including non viral (tRNK and ribozymes) and viral (retroviral and lentiviral vectors). In the past few years, iPSCs emerged as an interesting candidate for gene transfer. The feature that makes these cells appealing in the field of gene therapy is their susceptibility to gene correction by homologous recombination. Therapy protocols based on molecular basis of β-thalassemia are the best example of novel approaches in disease treatment.
Part of the book: Inherited Hemoglobin Disorders