GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease

2016/07/05 by Donna Oksenberg, Kobina Dufu, Mira P. Patel +16 · 26 citations
Medicine · #Hemoglobinopathies and Related Disorders #Erythrocyte Function and Pathophysiology #Blood groups and transfusion

paper · pdf · doi:10.1111/bjh.14214

Abstract

A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.

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