Fetal hemoglobin ≈ Fetal hemoglobin
View article
Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants Open
In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Hear…
View article
Survival in adults with sickle cell disease in a high-income setting Open
To the editor: Survival of patients with sickle cell disease (SCD) in high-income countries has improved greatly in the last 60 years. In 1960, it was described as a “disease of childhood”[1][1] whereas 25 years later, the Cooperative Stud…
View article
Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia Open
Significance We designed this study to elevate fetal hemoglobin for the treatment of β-thalassemia and sickle cell disease (SCD). It has long been known that some individuals who are compound heterozygotes of β-thalassemia or SCD with dele…
View article
Recent Advances in the Treatment of Sickle Cell Disease Open
Sickle cell anemia (SCA) was first described in the Western literature more than 100 years ago. Elucidation of its molecular basis prompted numerous biochemical and genetic studies that have contributed to a better understanding of its pat…
View article
Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human β-globin locus Open
Key Points CRISPR/Cas9-mediated disruption of the β-globin locus architecture reactivates fetal γ-globin expression in adult erythroblasts. Fetal γ-globin reactivation and sickle β-globin downregulation leads to the amelioration of the SCD…
View article
Genome editing of HBG1 and HBG2 to induce fetal hemoglobin Open
Key Points Cas9 editing of the γ-globin gene promoters in hematopoietic stem cells (HSCs) increases red cell HbF by ≤40%. No deleterious effects on hematopoiesis or off-target mutations were detected 16 weeks after xenotransplantation of e…
View article
Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype Open
Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopa…
View article
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells Open
A CRISPR screen for RBC regulators Hemoglobin in red blood cells (RBCs) carries oxygen to the tissues. Sickle cell disease is an inherited condition that involves abnormal hemoglobin. Current treatments entail modulating the level of fetal…
View article
Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study Open
ClinicalTrials.gov, NCT01685515.
View article
Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease Open
Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of…
View article
Sickle Cell Anemia and Its Phenotypes Open
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such kn…
View article
Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element Open
Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly …
View article
Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype Open
Editing the fetal γ-globin promoters in hematopoietic stem cells from sickle cell disease patients induces therapeutic γ-globin levels.
View article
CRISPR-Cas9 Editing of the <i>HBG1</i> and <i>HBG2</i> Promoters to Treat Sickle Cell Disease Open
CRISPR-Cas9 disruption of the HBG1 and HBG2 gene promoters was an effective strategy for induction of fetal hemoglobin. Infusion of autologous OTQ923 into three participants with severe sickle cell disease resulted in sustained induction o…
View article
Emerging Genetic Therapy for Sickle Cell Disease Open
The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, …
View article
Minireview: Genetic basis of heterogeneity and severity in sickle cell disease Open
Sickle cell disease, a common single gene disorder, has a complex pathophysiology that at its root is initiated by the polymerization of deoxy sickle hemoglobin. Sickle vasoocclusion and hemolytic anemia drive the development of disease co…
View article
Understanding Sickle cell disease: Causes, symptoms, and treatment options Open
Sickle cell disease (SCD) is a hereditary blood disorder characterized by the production of abnormal hemoglobin molecules that cause red blood cells to take on a crescent or sickle shape. This condition affects millions of people worldwide…
View article
Therapeutically relevant engraftment of a CRISPR-Cas9–edited HSC-enriched population with HbF reactivation in nonhuman primates Open
CRISPR-Cas9–edited hematopoietic stem cells produce long-term engraftment and fetal hemoglobin reactivation in nonhuman primates.
View article
Fetal hemoglobin in sickle cell anemia Open
Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene ha…
View article
Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies Open
Summary The major β‐haemoglobinopathies, sickle cell disease and β‐thalassaemia, represent the most common monogenic disorders worldwide and a steadily increasing global disease burden. Allogeneic haematopoietic stem cell transplantation, …
View article
A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease Open
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the diseas…
View article
Insight into the complex pathophysiology of sickle cell anaemia and possible treatment Open
Sickle cell anaemia ( SCA ) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, …
View article
Disruption of the BCL11A Erythroid Enhancer Reactivates Fetal Hemoglobin in Erythroid Cells of Patients with β-Thalassemia Major Open
In the present report, we carried out clinical-scale editing in adult mobilized CD34+ hematopoietic stem and progenitor cells (HSPCs) using zinc-finger nuclease-mediated disruption of BCL11a to upregulate the expression of γ-globin (fetal …
View article
KLF1 drives the expression of fetal hemoglobin in British HPFH Open
Key Points Introduction of the British HPFH mutation into the fetal globin promoter in a human cell model causes elevated fetal globin expression. The British HPFH mutation creates a de novo binding site both in vitro and in vivo for the p…
View article
In vivo HSPC gene therapy with base editors allows for efficient reactivation of fetal γ-globin in β-YAC mice Open
Base editors are capable of installing precise genomic alterations without creating double-strand DNA breaks. In this study, we targeted critical motifs regulating γ-globin reactivation with base editors delivered via HDAd5/35++ vectors. T…
View article
Cell and Gene Therapy for the Beta-Thalassemias: Advances and Prospects Open
The beta-thalassemias are inherited anemias caused by mutations that severely reduce or abolish expression of the beta-globin gene. Like sickle cell disease, a related beta-globin gene disorder, they are ideal candidates for performing a g…
View article
Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin Open
The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only antisickling drug approved since hydroxyure…
View article
Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers Open
Key Points Ldb1 transcription factor self-association domain fused to γ-globin promoter-specific ZF protein increases HbF, reduces HbS in hSCD cells. In vitro reactivation of HbF mediated by ZF-Ldb1 exceeds pharmacologic treatment in adult…
View article
A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy Open
Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyure…
View article
Gene therapy of hemoglobinopathies: progress and future challenges Open
Recently, gene therapy clinical trials have been successfully applied to hemoglobinopathies, such as sickle cell disease (SCD) and β-thalassemia. Among the great discoveries that led to the design of genetic approaches to cure these disord…