Evolving treatment paradigms in sickle cell disease

Jagadeeswaran, Ramasamy; Rivers, Angela

doi:10.1182/asheducation-2017.1.440

Cited by 22 publications

(21 citation statements)

References 58 publications

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“…The major source of intracellular ROS is the mitochondria in most cells ( 28 ) but mature red blood cells (RBCs) from healthy individuals extrude their mitochondria and other organelles during the terminal process of erythropoiesis ( 29 – 32 ). In contrast, a higher percentage of mature RBCs from SCD patients and mice retain their mitochondria leading to excessive ROS accumulation and oxidative stress ( 25 , 33 , 34 ). It has been shown that treatment with products of hemolysis including ferric Hb, ferryl Hb or heme causes bioenergetics changes, abnormal membrane permeability and ROS-induced lipid peroxidation in endothelial and alveolar cells mitochondria ( 35 , 36 ), which may contribute to inflammatory process and lung injury ( 37 , 38 ).…”

Section: Oxidative Stress and Hemolysis In Sickle Cell Diseasementioning

confidence: 99%

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Gbotosho¹,

Kapetanaki

Kato

2021

Front. Immunol.

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Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.

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Section: Oxidative Stress and Hemolysis In Sickle Cell Diseasementioning

confidence: 99%

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Gbotosho¹,

Kapetanaki

Kato

2021

Front. Immunol.

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“…There is growing recognition that SS RBCs experience oxidative stress throughout their lifetimes ( 31 ) and, unlike their normal AA counterparts, retain some mitochondria after maturation, which can be a major source for ROS ( 32 ). Consequently, the oxidative milieu, which also continues inside the circulating RBC-derived MPs, provides a fertile ground for the acceleration of HbS oxidation reactions ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Substitutions in the β subunits of sickle-cell hemoglobin improve oxidative stability and increase the delay time of sickle-cell fiber formation

Meng

Kassa

Strader

et al. 2019

Journal of Biological Chemistry

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After reacting with hydrogen peroxide (H2O2), sickle-cell hemoglobin (HbS, βE6V) remains longer in a highly oxidizing ferryl form (HbFe4+=O) and induces irreversible oxidation of “hot-spot” amino acids, including βCys-93. To control the damaging ferryl heme, here we constructed three HbS variants. The first contained a redox-active Tyr in β subunits (F41Y), a substitution present in Hb Mequon; the second contained the Asp (K82D) found in the β cleft of Hb Providence; and the third had both of these β substitutions. Both the single Tyr-41 and Asp-82 constructs lowered the oxygen affinity of HbS but had little or no effects on autoxidation or heme loss kinetics. In the presence of H2O2, both rHbS βF41Y and βF41Y/K82D enhanced ferryl Hb reduction by providing a pathway for electrons to reduce the heme via the Tyr-41 side chain. MS analysis of βCys-93 revealed moderate inhibition of thiol oxidation in the HbS single F41Y variant and dramatic 3- to 8-fold inhibition of cysteic acid formation in rHbS βK82D and βF41Y/K82D, respectively. Under hypoxia, βK82D and βF41Y/K82D HbS substitutions increased the delay time by ∼250 and 600 s before the onset of polymerization compared with the rHbS control and rHbS βF41Y, respectively. Moreover, at 60 °C, rHbS βK82D exhibited superior structural stability. Asp-82 also enhanced the function of Tyr as a redox-active amino acid in the rHbS βF41Y/K82D variant. We conclude that the βK82D and βF41Y substitutions add significant resistance to oxidative stress and anti-sickling properties to HbS and therefore could be potential genome-editing targets.

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“…RBC are oxygen carriers, which places them in constant danger from the cumulative impact of reactive oxygen species and free radicals formed by oxygen and hemoglobin metabolism inside the RBC. 56 Sickle RBC, due to their unique intracellular milieu with high concentrations of HbS forming and re-forming polymers, are at increased risk of oxidative damage. L-glutamine is an amino acid and a precursor used in the synthesis of glutathione and reduced nicotinamide adenine nucleotide diphosphate, which can protect the sickle RBC from oxidative damage.…”

Section: Red Blood Cell Intrinsic Targetsmentioning

confidence: 99%

Emerging disease-modifying therapies for sickle cell disease

Carden

Little

2019

Haematologica

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Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways ‘downstream’ to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute’s 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplantation in approximately 1,000 people, most of whom were children, and significantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of multimodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibition of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation proteins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sickle cell disease currently, or recently, tested in clinical trials in the era following approval of hydroxyurea.

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Evolving treatment paradigms in sickle cell disease

Cited by 22 publications

References 58 publications

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Substitutions in the β subunits of sickle-cell hemoglobin improve oxidative stability and increase the delay time of sickle-cell fiber formation

Emerging disease-modifying therapies for sickle cell disease

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