Abstract
β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.
Highlights
Abstract: β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE)
A broad spectrum of phenotype is observed in this condition, mainly defined by the degree of anaemia: transfusion-dependent β-thalassaemia (TDT) is characterized by a lifelong requirement for blood transfusions, while non-transfusion-dependent β-thalassaemia (NTDT) may require limited transfusions for a restricted period
We describe new treatments for ineffective erythropoiesis (IE) in β-thalassaemia, focusing on the biological mechanisms that have been recently described and the pharmacological compounds that have been developed in this field of clinical research
Summary
IE is the long-term result of a complex interplay of molecular mechanisms primarily involving the bone marrow and its articulate bidirectional crosstalk with the liver, spleen, and gut, eventually resulting in the production of pathological RBC. In β-thalassaemia patients, bone marrow contains about six times more erythroid precursors than normal, and apoptotic cell death is about four times higher than in a healthy subject [12]. Apoptosis of the erythroid precursors, triggered by the relative excess of α-globin chains, leads to medullary and intravascular haemolysis [13]. The altered differentiation of erythroid progenitors seems to exacerbate IE, combined with increased proliferation and apoptosis [14], leading to anaemia, extramedullary haematopoiesis, splenomegaly, and systemic iron overload [15]. Advanced characterisation of the molecular bases of these complex processes is, essential for the development of effective disease-modifying therapies (Figure 1)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
