Abstract

BACKGROUND

In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD.

OBJECTIVE

The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood).

METHODS

The mechanical and rheological properties of GBT440-treated SS RBCs were measured using micropipette and filtration techniques. The viscosity of sickle blood was measured using a Wells-Brookfield cone/plate viscometer.

RESULTS

GBT440 restored movement of deoxygenated SS RBCs through a gel filtration column and reduced the pressure required to pass SS RBCs through a polycarbonate filter. Moreover, GBT440 decreased the membrane shear elastic modulus of SS RBCs assessed via micropipette aspiration and reduced the hyperviscosity of SS blood under deoxygenated conditions.

CONCLUSIONS

GBT440 maintains SS RBC deformability and improves SS blood viscosity by inhibiting HbS polymerization under deoxygenated conditions. These results further support development of GBT440 as a disease-modifying agent in SCD patients.

MeSH

Erythrocytes, Membranes, Blood Cells

Cited by

• Drug Therapies for the Management of Sickle Cell Disease. F1000Res, 2020
• Biophysical and rheological biomarkers of red blood cell physiology and pathophysiology. Curr Opin Hematol, 2021
• Measuring success: utility of biomarkers in sickle cell disease clinical trials and care. Hematology Am Soc Hematol Educ Program, 2019
• First case of DRESS (drug reaction with eosinophilia and systemic symptoms) associated with voxelotor. Am J Hematol, 2021
• Time to rethink haemoglobin threshold guidelines in sickle cell disease. Br J Haematol, 2021
• The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease. Blood, 2024
• Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice. Am J Physiol Heart Circ Physiol, 2021
• Modulating hemoglobin allostery for treatment of sickle cell disease: current progress and intellectual property. Expert Opin Ther Pat, 2022
• Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients. Am J Hematol, 2020
• An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling. Biomolecules, 2021
• Voxelotor: A Ray of Hope for Sickle Disease. Cureus, 2020
• Promising role of voxelotor in managing sickle cell disease in children: a narrative review. Clin Exp Pediatr, 2024
• Resveratrol, a New Allosteric Effector of Hemoglobin, Enhances Oxygen Supply Efficiency and Improves Adaption to Acute Severe Hypoxia. Molecules, 2023
• GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia. Am J Transl Res, 2022
• Gene-environmental influence of space and microgravity on red blood cells with sickle cell disease. NPJ Genom Med, 2024
• The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia. J Clin Med, 2024
• VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Sci Rep, 2021
• A Review of Single-Cell Adhesion Force Kinetics and Applications. Cells, 2021
• Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor. Ther Adv Hematol, 2021
• A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood, 2019