β-Thalassaemia: emergence of new and improved iron chelators for treatment

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Abstract

β-Thalassaemia is an inherited blood disorder which through repeated blood transfusions and enhanced iron uptake from the gastrointestinal tract, results in marked iron overload. Untreated, the iron accumulation results in the dysfunction of vital organs such as the heart and liver. At present, the most effective treatment for β-thalassaemia is the use of the iron chelator, desferrioxamine, which is expensive, orally inactive and requires long subcutaneous infusions. In this concise review, we will focus on novel chelators which show therapeutic potential to replace desferrioxamine. Furthermore, we will discuss the potential of combined iron chelation therapy and the principle that, in the future, the use of more than just one chelator may be beneficial in tailoring individual iron chelation regimens.

Section snippets

General introduction and overview: β-thalassaemia results in iron overload

β-Thalassaemia is an inherited disorder of haemoglobin synthesis that was first documented by Drs. Thomas Cooley and Pearl Lee in 1925 (Weatherall, 1981; Olivieri & Brittenham, 1997). The disease is common in Mediterranean countries, the Middle East, the Indian subcontinent, South East Asia, Asian parts of Russia, and the northern-third of China (Weatherall, 1981; Olivieri & Brittenham, 1997). The ineffective erythropoiesis in β-thalassaemia is due to defective haemoglobin synthesis, leading to

Pathogenesis of β-thalassaemia

Patients with β-thalassaemia have a reduction or a lack of synthesis of the β-chain of haemoglobin while the α-chain synthesis remains unimpaired (Weatherall, 1981; Hoffbrand, Pettit, & Moss, 2001). The imbalance between α- and β-chain causes the α-chain to form unstable aggregates that precipitate and affect erythrocyte membrane plasticity (Hoffbrand et al., 2001). This leads to erythrocyte destruction in the bone marrow and spleen, resulting in ineffective erythropoiesis and anaemia (

Desferrioxamine

Iron overload diseases can be readily treated using chelation therapy. An ideal iron chelator should be orally effective, highly efficient, economical, specific for iron and show low toxicity. Currently, patients are treated with DFO (Fig. 2) which is the only widely used and approved iron chelator (Richardson, 1999). However, DFO has poor absorption capability across the gastrointestinal tract, rendering it orally ineffective (Richardson, 1999, Franchini et al., 2000). Apart from the

Conclusions

There has been no suitable replacement for DFO over the last few decades for the treatment of β-thalassaemia. However, chelating agents with better oral activity and efficacy have been designed and are undergoing development. These ligands may be used as alternatives to DFO or as agents that can be used alone or in combination to induce maximum iron excretion. Finally, in the future, the individual tailoring of chelation therapy to maximise iron excretion will benefit from having the choice of

Acknowledgements

Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children’s Hospital. This project was supported by a fellowship and project grant from the National Health and Medical Research Council of Australia and a commercial grant from Metabolic Pharmaceuticals Ltd., Melbourne. The authors thank Ms. Juliana Kwok of the Iron Metabolism and Chelation Program for her comments on the manuscript prior to submission.

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