Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

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.

TGF-beta signal transduction: biology, function and therapy for diseases

“…β-thalassaemia is a β-globin gene mutation that causes genetic disease, which is characterized by iron-loading anemia and ineffective erythropoiesis [176]. TGF-β is a negative regulatory factor in erythrocyte differentiation and maturation, similar to erythropoietin [177].…”

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

“…Alternatively, a growing evidence support the concept that induction of fetal hemoglobin (HbF) by pharmacological agents might be of great interest for the development of therapeutic protocols for β-thalassemia [18][19][20] . Induction of HbF has been the object of several studies and review papers [21][22][23] and at this stage there are several compounds that reached the stage of clinical testing, including sirolimus (see later), benserazide and thalidomide 20,24 . In this context, orphan drug designation, in addition to patent applications, is considered a parallel strategy to help the pharmaceutical development of drugs to be used for therapeutic treatment of β-thalassemia.…”

“…Alternatively, a growing evidence support the concept that induction of fetal hemoglobin (HbF) by pharmacological agents might be of great interest for the development of therapeutic protocols for β-thalassemia 18 – 20 . Induction of HbF has been the object of several studies and review papers 21 – 23 and at this stage there are several compounds that reached the stage of clinical testing, including sirolimus (see later), benserazide and thalidomide 20 , 24 .…”

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

“…Lentiviral vectors expressing the β-globin gene can be used to correct the phenotype of patients and genome and epigenome editing technologies are explored to alter globin gene regulation in order to reactivate HbF to mimic the protective effect of genetic traits typical of hereditary persistence of fetal hemoglobin (HPFH) condition. Finally, efficient CRISPR-Cas9-based genome editing of β-globin gene can also be obtained as demonstrated by Cosenza et al 17 Alternatively, a growing evidence support the concept that induction of fetal hemoglobin (HbF) by pharmacological agents might be of great interest for the development of therapeutic protocols for β-thalassemia [18][19][20] . Induction of HbF has been the object of several studies and review papers [21][22][23] and at this stage there are several compounds that reached the stage of clinical testing, including sirolimus (see later), benserazide and thalidomide 20,24 .…”

“…Finally, efficient CRISPR-Cas9-based genome editing of β-globin gene can also be obtained as demonstrated by Cosenza et al 17 Alternatively, a growing evidence support the concept that induction of fetal hemoglobin (HbF) by pharmacological agents might be of great interest for the development of therapeutic protocols for β-thalassemia [18][19][20] . Induction of HbF has been the object of several studies and review papers [21][22][23] and at this stage there are several compounds that reached the stage of clinical testing, including sirolimus (see later), benserazide and thalidomide 20,24 . In this context, orphan drug designation, in addition to patent applications, is considered a parallel strategy to help the pharmaceutical development of drugs to be used for therapeutic treatment of β-thalassemia.…”