Introduction to a review series on globin disorders

Globin disorders are the most common inherited cause of anemia worldwide. As much as 20% of the world population is estimated to carry mutations in one or more of the α-globin genes, and a further 1.5% have mutations in β-globin genes. The mutations and associated disorders are most commonly found in Asia, including the Indian subcontinent, as well as sub-Saharan Africa and the Mediterranean, but are increasingly affected by migration patterns throughout the world. Although the clinical manifestations of the globin disorders vary considerably, and recent advances in treatment have led to very significant improvements in many countries, the burden of disease in most parts of the world remains very high. For α-thalassemic mutations, the effects vary from an asymptomatic abnormality in the blood count in the case of 1 missing α-globin gene to death in utero in the case of α-thalassemia major.¹ For β-thalassemia major, survival has gone from <10 years in the 1960s to the same as that of the normal population with modern management of anemia and iron overload. Curative gene therapy approaches through modulation of fetal hemoglobin or introduction of fetal hemoglobin–like genes are now available for β-thalassemia and sickle cell disease.

The 4 articles in this review series address advances in our understanding of globin gene biology that are now beginning to translate into real and potential therapeutic benefits for patients. In each case, the starting point has been years of detailed investigation into the precise mechanisms involved in the regulation of these ancestrally important genes. Rather than attempting a comprehensive overview, the topics we have chosen reflect those areas of globin gene biology in which some of the most exciting, and often unexpected, advances have been made. The series includes the following articles.

• Ali Amid, Siyu Liu, Christian Babbs, and Douglas R. Higgs, “Hemoglobin Bart’s hydrops fetalis: charting the past and envisioning the future”

• Prabhodh S. Abbineni, Srishti Baid, and Mitchell J. Weiss, “A moonlighting job for α-globin in blood vessels”

• Eugene Khandros and Gerd A. Blobel, “Elevating fetal hemoglobin: recently discovered regulators and mechanisms”

• Valeria Maria Pinto, Filippo Mazzi, and Lucia De Franceschi, “Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders”

Amid et al discuss how increasing knowledge of the most severe of the α-globin gene disorders, Bart’s hydrops fetalis syndrome (BHFS), or α-thalassemia major now allows for the treatment of the severe anemia to be started in utero but, at the same time, leads to unique challenges, particularly in the long term.² They go on to outline potential strategies for curative therapy in BHFS based on recent advances in the understanding of the complex mechanisms regulating the expression of the genes in the α-globin gene cluster.

Abbineni et al discuss the fascinating and unexpected role of α-globin expression in the vasculature.³ They review the evidence supporting a physiological function for endothelial cell α-globin expression in modulating nitric oxide–mediated blood flow in mice and humans and the potential clinical relevance of these novel observations.

Khandros and Blobel discuss current and novel approaches to elevating fetal hemoglobin, where the clinical relevance in sickle cell disease and thalassemia is very well established.⁴ They focus specifically on the most recent developments in the field identifying the remarkable number of inputs converging directly or indirectly on γ-globin gene (HBG) to β-globin gene (HBB) switching mechanism, many of which have resulted from harnessing the power of CRISPR-Cas9–based screens.

Pinto et al discuss new therapeutic approaches to the management of β-globin disorders, including β-thalassemias and sickle cell disease.⁵ They focus in particular on active exploratory and confirmatory clinical trials and how advances in the treatment of thalassemia and sickle cell disease are now being extended to other inherited red cell disorders, such as congenital dyserythropoietic anemia and Diamond-Blackfan anemia.

Our knowledge of the molecular biology, physiology, and clinical management of hemoglobinopathies has advanced dramatically in the past decade, and we can manipulate this physiology and, in fact, the underlying genes to the benefit of patients with more severe disorders. We have also learned that even mild chronic anemia can lead to significant problems related to lack of oxygen delivery over many decades. So, there is a lot of work that remains to be done, but also a tremendous opportunity, particularly if the recent advances described in these reviews can be extended beyond the well-resourced countries to countries with the highest prevalence of disease.