Combined haptoglobin and hemopexin therapy for the treatment of cardiopulmonary dysfunction in sickle cell disease.

Hemolysis and the downstream consequences of cell-free hemoglobin (Hb) and heme contribute to the development of sickle cell disease pulmonary hypertension (SCD-PH). The plasma concentrations of Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hpx) in sickle cell patients are observed to be significantly lower than healthy donors. The unchecked exposure to Hb and heme contribute to vasculopathy and aberrant cardiac function. This is consistent with vascular remodeling co-localized within iron rich macrophages. Based on these observations in patients, we hypothesize that a joint Hb and heme scavenger approach, combining Hp + Hpx as a therapeutic will attenuate hemolysis driven SCD-PH progression in a SCD mouse model. To test the hypothesis, we utilized our validated Berk-SS mouse model of SCD-PH driven by a 10-week moderate hypoxia exposure and weekly subcutaneous administration of Hp + Hpx. At study termination, we analyzed changes in cardiopulmonary iron deposition, right ventricular and pulmonary functional parameters, and multi-omic indices associated with SCD-PH. Our data demonstrates that Hp+Hpx improves pulmonary vascular resistance and right ventricular function including stiffness, afterload, cardiac output, ventricular to vascular coupling ratio, pulmonary vascular resistance and medial hypertrophy. Histological evaluation of lung and right ventricular tissue demonstrates attenuation of cardiopulmonary pathology. Finally, a multi-omic analysis of whole lung and heart tissue demonstrates a rebalancing of proteins related to PH, iron, inflammation, and oxidative stress. This data provides strong pre-clinical evidence for the clinical study of combined Hb and heme scavenger proteins in the treatment of PH-associated SCD.