Dufu Kobina, Patel Mira, Oksenberg Donna, Cabrales Pedro
Global Blood Therapeutics Inc., South San Francisco, CA, USA.
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Clin Hemorheol Microcirc. 2018;70(1):95-105. doi: 10.3233/CH-170340.
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.
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).
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.
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.
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.
在镰状细胞病（SCD）中，血红蛋白S（HbS）的聚合导致形成僵硬、不可变形的镰状红细胞。红细胞可变形性丧失、镰状化和不可逆的膜损伤会导致异常的血液流变学，并增加粘度，这会导致血管阻塞和其他SCD病理生理学变化。GBT440（通用名：voxelotor）是一种新型的抗聚合和抗镰状化药物，目前正在进行治疗SCD的临床评估。
本研究的目的是确定GBT440对镰状红细胞（SS红细胞）可变形性和镰状细胞血（SS血）高粘度的影响。
使用微量移液器和过滤技术测量GBT440处理的SS红细胞的力学和流变学特性。使用Wells-Brookfield锥板粘度计测量镰状细胞血粘度。
GBT440恢复了脱氧SS红细胞通过凝胶过滤柱的运动，并降低了使SS红细胞通过聚碳酸酯过滤器所需的压力。此外，GBT440降低了通过微量移液器抽吸评估的SS红细胞的膜剪切弹性模量，并降低了脱氧条件下SS血的高粘度。
GBT440在脱氧条件下通过抑制HbS聚合来维持SS红细胞的可变形性并改善SS血粘度。这些结果进一步支持将GBT440开发为SCD患者的疾病修饰药物。
