title: GBT440 Inhibits Sickling of Sickle Cell Trait Blood UnderIn VitroConditions Mimicking Strenuous Exercise.
abstract: In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death. We report that GBT440, an agent being developed for the treatment of SCD, increases the affinity of oxygen for Hb and inhibitsin vitropolymerization of a mixture of HbS and HbA that simulates SCT blood. Moreover, GBT440 prevents sickling of SCT blood underin vitroconditions mimicking strenuous exercise with hypoxia, dehydration and acidosis. Together, our results indicate that GBT440 may have the potential to protect SCT individuals from sickling-related complications during conditions that favor HbS polymerization.
authors.affiliation: Global Blood Therapeutics Inc. , San Francisco, CA, USA.
authors.forename: Kobina
authors.initials: K
authors.lastname: Dufu
authors.affiliation: Global Blood Therapeutics Inc. , San Francisco, CA, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Lehrer-Graiwer
authors.affiliation: Global Blood Therapeutics Inc. , San Francisco, CA, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Ramos
authors.affiliation: Global Blood Therapeutics Inc. , San Francisco, CA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Oksenberg
keywords: Sickle cell trait; exertional sickling; hemoglobin oxygen affinity; rhabdomylosis; sickle cell disease