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Frontiers in Immunology 2020Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S... (Review)
Review
Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S (HbS), which polymerizes under deoxygenation, and induces the sickling of red blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently become anemic and develop frequent and recurrent vaso-occlusive crises. However, it is now evident that SCD is not only a RBC rheological disease. Accumulating evidence shows that SCD is also characterized by the presence of chronic inflammation and oxidative stress, participating in the development of chronic vasculopathy and several chronic complications. The accumulation of hemoglobin and heme in the plasma, as a consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs), which may activate endothelial inflammation through TLR-4 signaling and promote the development of complications, such as acute chest syndrome. It is also suspected that heme may activate the innate immune complement system and stimulate neutrophils to release neutrophil extracellular traps. A large amount of microparticles (MPs) from various cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into the plasma of SCD patients and participate in the inflammation and oxidative stress in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters the RBC properties. Increased pro-inflammatory cytokine concentrations promote the activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane and further alters the deformability of the cells, modifying their aggregation properties. These RBC rheological alterations have been shown to be associated to specific SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover, RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive to various inflammatory molecules that promote RBC dehydration and increase RBC adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle between abnormal RBC rheology and inflammation, which modulates the clinical severity of patients.
Topics: Anemia, Sickle Cell; Animals; Duffy Blood-Group System; Erythrocytes; Extracellular Traps; Hemoglobin, Sickle; Hemolysis; Humans; Inflammation; Mice; Oxidative Stress; Reactive Oxygen Species; Receptors, Cell Surface
PubMed: 32231672
DOI: 10.3389/fimmu.2020.00454 -
Blood Apr 2023Sickle cell disease (SCD) is a monogenic disease caused by a nucleotide mutation in the β-globin gene. Current gene therapy studies are mainly focused on lentiviral...
Sickle cell disease (SCD) is a monogenic disease caused by a nucleotide mutation in the β-globin gene. Current gene therapy studies are mainly focused on lentiviral vector-mediated gene addition or CRISPR/Cas9-mediated fetal globin reactivation, leaving the root cause unfixed. We developed a vectorized prime editing system that can directly repair the SCD mutation in hematopoietic stem cells (HSCs) in vivo in a SCD mouse model (CD46/Townes mice). Our approach involved a single intravenous injection of a nonintegrating, prime editor-expressing viral vector into mobilized CD46/Townes mice and low-dose drug selection in vivo. This procedure resulted in the correction of ∼40% of βS alleles in HSCs. On average, 43% of sickle hemoglobin was replaced by adult hemoglobin, thereby greatly mitigating the SCD phenotypes. Transplantation in secondary recipients demonstrated that long-term repopulating HSCs were edited. Highly efficient target site editing was achieved with minimal generation of insertions and deletions and no detectable off-target editing. Because of its simplicity and portability, our in vivo prime editing approach has the potential for application in resource-poor countries where SCD is prevalent.
Topics: Mice; Animals; Gene Editing; CRISPR-Cas Systems; Anemia, Sickle Cell; Hematopoietic Stem Cells; Hemoglobin, Sickle
PubMed: 36800642
DOI: 10.1182/blood.2022018252 -
American Journal of Hematology Nov 2022
Topics: Hemoglobin SC Disease; Hemoglobin, Sickle; Humans
PubMed: 36073655
DOI: 10.1002/ajh.26702 -
The Lancet. Global Health Jan 2022
Topics: Developing Countries; Hemoglobin, Sickle; Hemoglobinopathies; Humans; Infant, Newborn; Neonatal Screening
PubMed: 34919844
DOI: 10.1016/S2214-109X(21)00559-3 -
Biomolecules Feb 2023Sickle cell disease is the consequence of a single point mutation on the surface of the β chains of the hemoglobin molecule leading to the formation of rigid polymers... (Review)
Review
Sickle cell disease is the consequence of a single point mutation on the surface of the β chains of the hemoglobin molecule leading to the formation of rigid polymers that disrupt circulation. It has long been established that the polymers are comprised of seven pairs of double strands that are twisted replicas of the double strands found in crystals. Here, we review several newer developments that elaborate on that simple model and provide deeper insights into the process.
Topics: Humans; Hemoglobin, Sickle; Anemia, Sickle Cell; Hemoglobins; Polymers; Point Mutation
PubMed: 36979347
DOI: 10.3390/biom13030413 -
Molecular Aspects of Medicine Apr 2022Basic research on hemoglobin has been essential for understanding the origin and treatment of many hematological disorders due to abnormal hemoglobins. The most... (Review)
Review
Basic research on hemoglobin has been essential for understanding the origin and treatment of many hematological disorders due to abnormal hemoglobins. The most important of the hemoglobinopathies is sickle cell disease - Linus Pauling's "molecular disease" that gave birth to molecular medicine. In this review, I will describe the contributions of basic biophysical research on normal and sickle cell hemoglobin (HbS) to understanding the molecular pathogenesis of the disease and providing the conceptual basis for the various approaches to drug therapy that target HbS polymerization. Most prominent among these are the experimental results on the solubility of HbS as a function of oxygen saturation explained by the allosteric model of Monod, Wyman, and Changeux and the Gill-Wyman thermodynamic linkage relation between solubility and oxygen binding, the solubility of mixtures of HbS with normal or fetal hemoglobin explained by Minton's thermodynamic model, and the highly unusual kinetics of HbS polymerization explained by a novel double nucleation mechanism that also accounts for the aggregation kinetics of the Alzheimer's peptide. The HbS polymerization kinetics are of great importance to understanding the pathophysiology and clinical course, as well as guiding drug development for treating this common and severe disease. The article focuses primarily on experimental and theoretical results from my lab, so it is not a comprehensive review of the subject.
Topics: Anemia, Sickle Cell; Hemoglobin, Sickle; Hemoglobins; Humans; Kinetics; Thermodynamics
PubMed: 34274158
DOI: 10.1016/j.mam.2021.100971 -
Molecules (Basel, Switzerland) Dec 2019Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino... (Review)
Review
Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12- and 15-mers under consideration in recent years.
Topics: Anemia, Sickle Cell; Antisickling Agents; Drug Design; Hemoglobin, Sickle; Humans; Peptides
PubMed: 31842406
DOI: 10.3390/molecules24244551 -
Hematology. American Society of... Dec 2017Sickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia,... (Review)
Review
Sickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia, vaso-occlusive painful crisis, and multiorgan damage. In SCD, an increased reactive oxygen species (ROS) generation occurs both inside the red blood cells and inside the vascular lumen, which augment hemolysis and cellular adhesion. This review discusses the evolving body of literature on the role of ROS in the pathophysiology of SCD as well as some emerging therapeutic approaches to SCD with a focus on the reduction of ROS.
Topics: Anemia, Sickle Cell; Cell Adhesion; Erythrocytes, Abnormal; Hemoglobin, Sickle; Hemolysis; Humans; Reactive Oxygen Species
PubMed: 29222291
DOI: 10.1182/asheducation-2017.1.440 -
Blood Nov 2022
Topics: Humans; Toll-Like Receptor 4; Monocytes; Hemoglobin, Sickle; Anemia, Sickle Cell; Inflammation; Cytokines
PubMed: 36326792
DOI: 10.1182/blood.2022018078 -
Haematologica Sep 2019The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxygenated sickle hemoglobin. A... (Review)
Review
The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxygenated sickle hemoglobin. A logical approach to disease modification is, therefore, to interdict this root cause. Ideally, such interdiction would utilize small molecules that are practical and accessible for worldwide application. Two types of such small molecule strategies are actively being evaluated in the clinic. The first strategy intends to shift red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and towards fetal hemoglobin, which inhibits sickle hemoglobin polymerization by a number of mechanisms. The second strategy intends to chemically modify sickle hemoglobin directly in order to inhibit its polymerization. Important lessons have been learnt from the pre-clinical and clinical evaluations to date. Open questions remain, but this review summarizes the valuable experience and knowledge already gained, which can guide ongoing and future efforts for molecular mechanism-based, practical and accessible disease modification of sickle cell disease.
Topics: Anemia, Sickle Cell; Antisickling Agents; DNA Methylation; Drug Design; Epigenesis, Genetic; Fetal Hemoglobin; Hemoglobin, Sickle; Histone Deacetylases; Humans; Hydroxyurea; Polymerization; gamma-Globins
PubMed: 31399526
DOI: 10.3324/haematol.2018.207530