A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic

Yasara, Nirmani; Premawardhena, Anuja; Mettananda, Sachith

doi:10.1186/s13023-021-01757-w

Cited by 33 publications

(22 citation statements)

References 105 publications

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“…Other encouraging features of hydroxyurea as an adjunct treatment for transfusion dependent β-thalassaemia are the vast experience of its use for other indications, availability and low cost. Hydroxyurea is an FDA approved drug that has been in use for cancers and sickle cell diseases for many decades 11 . It is widely available and is priced low.…”

Section: Discussionmentioning

confidence: 99%

“…Hydroxyurea is an antimetabolite S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme. It has shown to upregulate human γ-globin and fetal haemoglobin (HbF) synthesis in several in vitro and in vivo studies in patients with sickle cell disease 11 , 12 . Similarly, hydroxyurea induces HbF and reduces the blood transfusion requirement in some patients with non-transfusion-dependent β-thalassaemia 13 .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its effect on HbF, hydroxyurea has been shown to improve haemorheology and inhibit ineffective erythropoiesis in patients with sickle cell disease and β-thalassaemia. At the cellular level, hydroxyurea alters epigenetics and proteomics to promote the synthesis of antioxidants, structural proteins, carbonic anhydrase and proteins required for protein repair, which may contribute to its beneficial effects on ineffective erythropoiesis 11 .…”

Section: Introductionmentioning

confidence: 99%

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A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Yasara

Wickramarathne

Mettananda

et al. 2022

Sci Rep

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Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Yasara

Wickramarathne

Mettananda

et al. 2022

Sci Rep

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“…Positive but highly variable effects of hydroxyurea were observed in TD and NTDT patients in terms of total Hb content and improvement of other RBC indices. A positive effect of hydroxyurea in reducing the risk of leg ulcers, pulmonary hypertension, and osteoporosis emerged from a study in a large cohort of NTDT patients [93]. Furthermore, several case reports showed efficacy of hydroxyurea in treating masses of extramedullary haematopoiesis [94].…”

Section: Hydroxyureamentioning

confidence: 99%

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

Longo

Piolatto

Ferrero

et al. 2021

IJMS

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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.

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“…To overcome the challenges of HSCT and traditional gene therapy, several new approaches to treat β-thalassaemia are being studied. Inhibition of ineffective erythropoiesis by activin IIB receptor-ligand trap luspatercept, induction of fetal haemoglobin by hydroxyurea, upregulation of γ-globin by epigenetic drugs and genome editing of suppressors of γ-globin are notable examples ( Piga et al, 2019 ; Cappellini et al, 2020 ; Yasara et al, 2020 ; Frangoul et al, 2021 ; Yasara et al, 2021 ). An alternative pathway that has shown promise is silencing of α-globin.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Therapies for β-Thalassaemia by Altering the Expression of α-Globin Gene

Mettananda

2021

Front. Genome Ed.

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β-Thalassaemia is caused by over 300 mutations in and around the β-globin gene that lead to impaired synthesis of β-globin. The expression of α-globin continues normally, resulting in an excess of α-globin chains within red blood cells and their precursors. These unpaired α-globin chains form unstable α-hemichromes that trigger cascades of events to generate reactive oxygen species, leading to ineffective erythropoiesis and haemolysis in patients with β-thalassaemia. The clinical genetic data reported over several decades have demonstrated how the coinheritance of α-thalassaemia ameliorates the disease phenotype of β-thalassaemia. Thus, it is evident that down-regulation of the α-globin gene expression in patients with β-thalassaemia could ameliorate or even cure β-thalassaemia. Over the last few years, significant progress has been made in utilising this pathway to devise a cure for β-thalassaemia. Most research has been done to alter the epigenetic landscape of the α-globin locus or the well-characterised distant enhancers of α-globin. In vitro, pre-clinical studies on primary human erythroid cells have unveiled inhibition of histone lysine demethylation and histone deacetylation as potential targets to achieve selective downregulation of α-globin through epigenetic drug targeting. CRISPR based genome editing has been successfully used in vitro to mutate α-globin genes or enhancers of α-goblin to achieve clinically significant knockdowns of α-globin to the levels beneficial for patients with β-thalassaemia. This review summarises the current knowledge on the regulation of human α-globin genes and the clinical genetic data supporting the pathway of targeting α-globin as a treatment for β-thalassaemia. It also presents the progress of epigenetic drug and genome editing approaches currently in development to treat β-thalassaemia.

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A comprehensive review of hydroxyurea for β-haemoglobinopathies: the role revisited during COVID-19 pandemic

Cited by 33 publications

References 105 publications

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

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

Genetic and Epigenetic Therapies for β-Thalassaemia by Altering the Expression of α-Globin Gene

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