Increased hemoglobin affinity for oxygen with GBT1118 improves hypoxia tolerance in sickle cell mice

Therapeutic agents that increase the Hb affinity for oxygen (C2) could, in theory, lead to decreased C2 release from Hb and impose a hypoxic risk to tissues. In this study, GBT1118, an allosteric modifier of Hb affinity for C2, was used to assess the impact of increasing Hb affinity for C2 on brain tissue oxygenation, blood pressure, heart rate, C2 delivery, and tolerance to hypoxia in Townes transgenic sickle cell disease (SCD) mice. Brain oxygenation and C2 delivery were studied during normoxia and severe hypoxic challenges. Chronic treatment with GBT1118 increased Hb affinity for C2, reducing the PC2 for 50% HbC2 saturation (P50) in SCD mice from 31mmHg to 18mmHg. This treatment significantly reduced anemia, increasing hematocrit by 33%, improved cardiac output (CO), and C2 delivery and extraction. Chronically increasing Hb affinity for C2 with GBT1118 preserved cortical C2 tension during normoxia, improved cortical C2 tension during hypoxia, and increased tolerance to severe hypoxia in SCD mice. Independent of hematological changes induced by chronic treatment, a single dose of GBT1118 significantly improved tolerance to hypoxia, highlighting the benefits of increasing Hb affinity for C2 and consequently reducing sickling of RBCs in blood during hypoxia in SCD. NEW & NOTEWORTHY Chronic pharmacologically increased hemoglobin affinity for oxygen in sickle cell disease mice alleviated hematological consequences of sickle cell disease, increasing RBC half-life, hematocrit, and hemoglobin concentration, while also decreasing reticulocyte count. Additionally, chronically increased hemoglobin affinity for oxygen significantly improved survival as well as cortical tissue oxygenation in sickle cell disease mice during hypoxia, suggesting that oxygen delivery and utilization is improved by increased hemoglobin affinity for oxygen.