Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Li, Quan; Henry, Eric R.; Hofrichter, James; Smith, J. F.; Cellmer, Troy; Dunkelberger, Emily B.; Metaferia, Belhu; Jones-Straehle, Stacy; Boutom, Sarah; Christoph, Garrott W.; Wakefield, Terri H.; Link, Mary E.; Staton, Dwayne; Vass, E; Miller, Jeffery L.; Hsieh, Matthew M.; Tisdale, John F.; Eaton, William A.

doi:10.1073/pnas.1619054114

Cited by 41 publications

(88 citation statements)

References 57 publications

(50 reference statements)

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“…For therapeutic strategies other than the promotion of HbF synthesis, drug discovery could be accelerated by carrying out screens with intact red cells, such as the recently reported laser photolysis method for measuring sickling times of HbAS cells. 96 A method that is less technically demanding is currently under development at the National Institutes of Health. Even a 10% increase in cell volume is predicted to have a therapeutic effect.…”

Section: Resultsmentioning

confidence: 99%

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Treating sickle cell disease by targeting HbS polymerization

Eaton

Bunn

2017

Blood

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Although the root cause of sickle cell disease is the polymerization of hemoglobin S (HbS) to form fibers that make red cells less flexible, most drugs currently being assessed in clinical trials are targeting the downstream sequelae of this primary event. Less attention has been devoted to investigation of the multiple ways in which fiber formation can be inhibited. In this article, we describe the molecular rationale for 5 distinct approaches to inhibiting polymerization and also discuss progress with the few antipolymerization drugs currently in clinical trials.

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Section: Resultsmentioning

confidence: 99%

“…A new and sensitive sickling time assay has shown that potentially therapeutic levels of inhibition can be achieved at subnanomolar concentrations of ionophores, making increase in red cell volume a viable approach to therapy. 96 …”

Section: Reduce Intracellular Hb Concentrationmentioning

confidence: 99%

Treating sickle cell disease by targeting HbS polymerization

Eaton

Bunn

2017

Blood

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179

210

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“…This reasoning does not only bring HbS polymerization within the purview of non-covalent inhibition, but it also rationalizes why antisickling effects have been observed for various small molecular weight inhibitors [98][99][100]. For instance, screening for non-covalent antisickling agents that reverse HbS polymerization by altering RBC shape and volume (towards more spherical structures with larger volumes) discovered antisickling properties for gramicidin A and monensin A at concentrations of 200 pM and 2 nm, respectively [101]. Another example is the aggregation inhibition by HbF, which is required to be present in a just a little fraction (0.2) of total hemoglobin of SCD patients to achieve clinical resolution of symptoms [102,103].…”

Section: Hbs Aggregation Is An Inefficient Processmentioning

confidence: 90%

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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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.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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“…In particular, heterozygous conditions produce far greater distortions in the sickled cells than homozygous SS cells, a fact which is utilized in a current drug assay. [29] The differences within a given genotype might well be the consequence of the history of a given patient that shaped the particular cellular population at the time of observation. While this variable is viewed as confounding in the attempt to ascertain the presence of the S allele, it might actually provide unexpected insights, to the extent that the patients with longer transits might have a more severe course of the disease.…”

Section: Discussionmentioning

confidence: 99%

The flow of sickle blood through glass capillaries: a point of care application

Brown

Aprelev

Ferrone

2019

Preprint

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We show that the characteristic time for sickled blood to traverse 100 µm-diameter glass capillaries can be used as the foundation for a useful point-of-care diagnosis for sickle cell disease. 3.2 cm long capillaries were inserted into a 5 µL drop of blood, and 1/4 µL was spontaneously drawn into the tube. The rate at which the blood traversed the capillary was significantly changed by deoxygenation only for sickle genotypes, a consequence of the increased viscosity of cells containing sickle fibers. Under these conditions, we find deoxygenation causes the time for sickle blood to traverse the capillary to increase to about 3 times its original value, in contrast to normal blood, where the times are equivalent regardless of state of oxygenation. This corresponds to readily-observed time differences of around 10 s for capillary traversal. Such changes are present for blood from homozygous sickle cell patients, as well as heterozygous patients with hemoglobin AS, SC, and Sβ+ thalassemia. Moreover, we demonstrate that this test is sensitive to sickling therapies that increase the production of fetal Hb. This viscosity-based measurement thus offers the prospect of an assay that is 10 times faster than any current test of which we are aware, at costs that rival the least expensive of any current assays.

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Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Cited by 41 publications

References 57 publications

Treating sickle cell disease by targeting HbS polymerization

Treating sickle cell disease by targeting HbS polymerization

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

The flow of sickle blood through glass capillaries: a point of care application

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