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a-Globin as a molecular target in the treatment of b-thalassemia

Thalassemia is the most common form of all inherited disorders of the red cell. It is estimated that 70 000 children are bornwith various forms of thalassemia each year, andmore than half of these births are affected by severe formsofb-thalassemia, ofwhich themost common subgroup is hemoglobin (Hb) E b-thalassemia. Thalassemia was originally confined to the tropical and subtropical regions of theworld, distributed throughout the Mediterranean, sub-Saharan Africa, the Middle East, and the southern regions of Asia. However, as a result of relatively recent migration, many north European and North American countries are now home to large numbers of patients with thalassemia. Despite being one of thefirstmolecular diseases to be identified and have its pathophysiology understood, themanagement ofb-thalassemia still largely depends on supportive care, with regular lifelong red blood cell transfusions and iron chelation. In economically poor countries, affected individuals still die as children. However, even in developed countries, most patients with b-thalassemia still have reduced life expectancy and often experience a relatively poor quality of life. Allogeneic bone marrow transplantation, the only curative treatment option, is not feasible for most patients, even in economically developed countries, because of a lack of suitable donors. Furthermore, this treatment is still associated with a significant risk for mortality and morbidity, especially when the donor is not related. Over the course of the last 30 years, many new and experimental approaches to the treatment of thalassemia have been considered and developed; however, none has progressed to the level of significant clinical use. Gene therapy has made noteworthy, albeit slow, progress and is being tested in clinical trials in a limited number of patients. However, the reported risks associated with the procedure, including development of leukemia by activation of proto-oncogenes, means much further work will be required to develop this as a common treatment. Pharmacological augmentation of fetal hemoglobin (HbF) production has been a long-standing therapeutic objective and is already in clinical use for patients with severe sickle cell disease. Three different classes of HbF-inducing agents have been tested in patientswith thalassemia, includingchemotherapeutics/hypomethylating agents (hydroxyurea, 5-azacytidine, and decitabine), short chain fatty acid derivatives (sodium phenylbutyrate), and erythropoietin; however, with the exception of hemoglobin S b-thalassemia, none has been able to produce a sustainable clinical response. There has been a report of activation of d-globin gene expression in an animal model to enhance production of HbA2, but its clinical usefulness needs further consideration. Hence, it is clear there is still a great need for new, alternative, and effective therapeutic strategies for treatment of this life-limiting disease to render patients transfusionindependent and able to live a normal life. In patients with b-thalassemia, the primary damage to the red cells and their precursors is mediated via excess a-globin chains that accumulate when b-globin expression is reduced. A number of casecontrol and cohort studies have demonstrated that a natural reduction in a-globin chain output, resulting from coinherited a-thalassemia, is beneficial in patients with b-thalassemia (described in detail here). Therefore, reducing a-globin chains in patients with b-thalassemia is a potential pathway to developing new therapies. Advances in our understanding of the precise epigenetic regulation ofaandb-globin genes in erythroid cells, development of new drugs targeting specific epigenetic pathways, and the advent of genome engineering using programmable, sequence-specific endonucleases make it possible to consider new strategies for selective control of a-globin expression in patients with b-thalassemia. In this review, we summarize current molecular and clinical data rationalizing the use ofa-globin as a valid target in treatment of b-thalassemia and present plausible new strategies that can be used to achieve this goal.