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Fetal hemoglobin (HbF) induction therapy has become the most promising strategy for treating β-hemoglobinopathies, including sickle-cell diseases and β-thalassemia. However, subtle but critical structural difference exists between HbF and normal adult hemoglobin (HbA), which inevitably leads to reduced binding of the endogenous modulator 2,3-bisphosphoglycerate (2,3-BPG) to HbF and thus increased oxygen affinity and decreased oxygen transport efficiency of HbF. We combined the oxygen equilibrium experiments, resonance Raman (RR) spectroscopy, and molecular docking modeling, and we discuss 2 phthalides, z-butylidenephthalide and z-ligustilide, that can effectively lower the oxygen affinity of HbF. They adjust it to a level closer to that of HbA and make it a more satisfactory oxygen carrier for adults. From the oxygen equilibrium curve measurements, we show that the 2 phthalides are more effective than 2,3-BPG for modulating HbF. The RR spectra show that phthalides allosterically stabilize the oxygenated HbF in the low oxygen affinity conformation, and the molecular docking modeling reveals that the 2 chosen phthalides interact with HbF via the cleft around the γ 1 /γ 2 interface with a binding strength ∼1.6 times stronger than that of 2,3-BPG. We discuss the implications of z-butylidenephthalide and z-ligustilide in boosting the efficacy of HbF induction therapy to mitigate the clinical severities of β-hemoglobinopathies., (© 2019 by The American Society of Hematology.)

Sickle cell disease and thalassemia have distinctly different mutations, but both share common complications from a chronic vasculopathy. In the past, fetal hemoglobin-modulating drugs have been the main focus of new therapy, but the increased understanding of the complex pathophysiology of these diseases has led to the development of novel agents targeting multiple pathways that cause vascular injury. This review explores the pathophysiology of hemoglobinopathies and novel drugs that have reached phase 1 and 2 clinical trials. Therapies that alter cellular adhesion to endothelium, inflammation, nitric oxide dysregulation, oxidative injury, altered iron metabolism, and hematopoiesis will be highlighted. To evaluate these therapies optimally, recommendations for improving clinical trial design in hemoglobinopathies are discussed.

The outlook for patients with sickle cell disease has improved steadily during the last two decades. In spite of these improvements, curative therapies are currently available only to a small minority of patients. The main theme of this chapter is to describe new therapeutic options that are at different stages of development that might result in further improvements in the outlook for patients with these disorders. Dr. Joseph DeSimone and his colleagues had previously made the important observation that the hypomethylating agent 5-azacytidine can reverse the switch from adult to fetal hemoglobin in adult baboons. Although similar activity was demonstrated in patients with sickle cell disease and beta-thalassemia, concern about the toxicity of 5-azacytidine prevented its widespread use in these disorders. In Section I, Dr. DeSimone discusses the role of DNA methylation in globin gene regulation and describe recent clinical experience with decitabine (an analogue of 5-azacytidine) in patients with sickle cell disease. These encouraging studies demonstrate significant fetal hemoglobin inducing activity of decitabine in patients who fail to respond to hydroxyurea. In Section II, Dr. George Atweh continues the same theme by describing recent progress in the study of butyrate, another inducer of fetal hemoglobin, in patients with sickle cell disease and beta-thalassemia. The main focus of his section is on the use of a combination of butyrate and hydroxyurea to achieve higher levels of fetal hemoglobin that might be necessary for complete amelioration of the clinical manifestations of these disorders. Dr. Atweh also describes novel laboratory studies that shed new light on the mechanisms of fetal hemoglobin induction by butyrate. In Section III, Dr. Ronald Nagel discusses the different available transgenic sickle mice as experimental models for human sickle cell disease. These experimental models have already had a significant impact on our understanding of the pathophysiology of sickle cell disease. Dr. Nagel describes more recent studies in which transgenic sickle mice provide the first proof of principle that globin gene transfer into hematopoietic stem cells inhibits in vivo sickling and ameliorates the severity of the disease. Although stroke in adult patients with sickle cell disease is not as common as in children, adult hematologists, like their pediatric colleagues, need to make management decisions in adult patients with a stroke or a history of stroke. Dr. Robert Adams has led several large clinical studies that investigated the role of transfusions in the prevention of stroke in children with sickle cell disease. Much less is known, however, about the prevention of first or subsequent strokes in adult patients with sickle cell disease. In Section IV, Dr. Adams provides some general guidelines for the management of adult patients with stroke while carefully distinguishing between recommendations that are evidence-based and those that are anecdotal in nature.