Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

Mouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human [a]-, {beta}- and {gamma}-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.