GBT440

Our Approach to SCD

SCD manifests in individuals who inherit at least one sickle hemoglobin (HbS) gene from a parent and an additional mutation on the second beta globin gene from the other parent. The HbS mutation confers a change in the shape of hemoglobin in its deoxygenated state, which causes deoxygenated hemoglobin molecules to polymerize (stick together). This polymerization is the mechanism by which HbS causes red blood cell (RBC) sickling, leading to the clinical manifestations of SCD.

Scientists have demonstrated that maintaining hemoglobin in an oxygenated state prevents HbS from polymerizing. Based on this finding, we believe that the ability to increase the proportion of hemoglobin that remains in an oxygenated state could potentially delay the HbS polymerization. In turn, we believe this would potentially prevent the sickling of RBCs, which may ameliorate, if not halt, all of the clinical manifestations of the disease. This hypothesis is based on multiple observations found in nature.

First, fetal hemoglobin is present during fetal development and persists for up to six to nine months in infants until it is replaced by adult hemoglobin. This fetal hemoglobin has an inherent high affinity for oxygen, which allows the developing fetus to capture oxygen from the mother’s blood. It has been observed that newborns with SCD do not experience RBC sickling until approximately six to nine months of age, after which fetal hemoglobin, with its high affinity for oxygen, is no longer expressed.

Second, there are rare individuals who have inherited both the sickle hemoglobin mutation and a gene deletion that allows them to continue to express 20% or more fetal hemoglobin in their RBCs into adulthood. It has been observed that these individuals do not exhibit the clinical manifestations of SCD, despite having the sickle gene mutation and 80% sickled hemoglobin in their blood.

With these natural examples in mind, GBT440 was designed to bind to approximately 20% of the total hemoglobin in a patient’s blood, thus increasing its affinity for oxygen and delaying polymerization of HbS. Importantly, we believe based on our non-clinical animal studies that approximately 20% to 40% modification would likely not adversely compromise oxygen delivery to the tissues.