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• W17161741 abstract "Abstract Background The polymerization of hemoglobin S results in red cell morphological changes and fragility, which promotes hemolysis. Aes-103 (5-hydroxymethylfurfural, 5-HMF) is a clinical-stage candidate anti-sickling agent that binds to alpha subunits of hemoglobin, increases its oxygen affinity and stabilizes the R-state. In vitro at, millimolar levels, it inhibits hypoxia-induced sickling and in vivo protects sickle cell mice against hypoxia-induced death. We have found in vitro that Aes-103 increases oxygen affinity of red cells from healthy control subjects and from patients with sickle cell disease either on or off hydroxyurea. We further investigated the ability of Aes-103 to protect red cells from patients with sickle cell anemia from a variety of effects of sickling. First, we used transmission electron microscopy (TEM) to investigate fiber formation in human sickle blood incubated with 5 mM Aes-103 for one hour at 37° prior to deoxygenation (2% oxygen for two hours) and fixed with glutaraldehyde, and embedded by standard techniques. Semi-quantitative analysis of the images showed that the addition of Aes-103 was able to significantly reduce the percentage of cells displaying elongated fibers (p=0.048). Furthermore, we confirmed that Aes-103 incubation prior to hypoxia also reduces morphological sickling as quantified by sickle imaging flow cytometry (P=0.0027). Fiber formation was associated with morphological sickling (R=0.522, P=0.027). Second, we investigated the effects of Aes-103 on sickle erythrocyte fragility. In vitro shear stress induced by rotation on a vertical rotator at 21 revolutions per minute for 3 hours promoted hemolysis in blood samples from patients with SCA (free hemoglobin 29.4 ± 3.4 vs. 8.4 ± 0.9 mM, p<0.001, n=10). Addition of Aes-103 at increasing concentrations for one hour prior to testing reduced the extent of shear-stress induced hemolysis, ranging from decreases of 15% at 1 mM to 28% at 2mM to 37% at 5 mM (p<0.001). Interestingly, although shear stress promoted less hemolysis in blood samples from healthy controls, Aes-103 reduced hemolysis in healthy control blood to a comparable extent, suggesting a red cell stabilizing mechanism distinct from any anti-sickling effect. Third, we evaluated the degree of hemolysis associated with erythrocyte sickling induced by deoxygenation. Hypoxia (2% oxygen for 2 hours) induced hemolysis, and the severity of hemolysis was reduced by the addition of Aes-103 for one hour (prior to hypoxia) at increasing concentrations up to 5 mM (free hemoglobin 31.3 ± 2.9 vs. 21.3 ± 2.8 mM, p = .002, n=11). In summary, treatment of sickle blood with Aes-103 in vitro, decreases fiber formation, increases oxygen affinity of sickle red cells, reduces sickle cell mechanical fragility, and reduces hemolysis caused by hypoxia-induced sickling. Aes-103 merits investigation as a potential alternative or adjunct to hydroxyurea as a treatment for sickle cell disease. We have completed a phase I clinical trial of oral Aes-103 at the NIH Clinical Center, and a separate abstract reports its apparent safety and tolerability. A phase 2 twenty-eight day study is being initiated in the U.K. in adults with sickle cell anemia. Disclosures: No relevant conflicts of interest to declare." @default.
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• W17161741 date "2013-11-15" @default.
• W17161741 modified "2023-10-04" @default.
• W17161741 title "The Anti-Sickling Agent Aes-103 Decreases Sickle Erythrocyte Fragility, Hypoxia-Induced Sickling and Hemolysis In Vitro" @default.
• W17161741 doi "https://doi.org/10.1182/blood.v122.21.940.940" @default.
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