In Humanized Sickle Cell Mice, Imatinib Protects Against Sickle Cell–Related Injury

Abstract

Drug repurposing is a valuable strategy for rare diseases. Sickle cell disease (SCD) is a rare hereditary hemolytic anemia accompanied by acute and chronic painful episodes, most often in the context of vaso-occlusive crisis (VOC). Although progress in the knowledge of pathophysiology of SCD have allowed the development of new therapeutic options, a large fraction of patients still exhibits unmet therapeutic needs, with persistence of VOCs and chronic disease progression. Here, we show that imatinib, an oral tyrosine kinase inhibitor developed for the treatment of chronic myelogenous leukemia, acts as multimodal therapy targeting signal transduction pathways involved in the pathogenesis of both anemia and inflammatory vasculopathy of humanized murine model for SCD. In addition, imatinib inhibits the platelet-derived growth factor-B–dependent pathway, interfering with the profibrotic response to hypoxia/reperfusion injury, used to mimic acute VOCs. Our data indicate that imatinib might be considered as possible new therapeutic tool for chronic treatment of SCD.

Mitapivat reprograms the RBC metabolome and improves anemia in a mouse model of hereditary spherocytosis

“…As shown in Figure 3D , mitapivat significantly reduced the in vitro release of erythroid vesicle from 4.2 –/– mouse erythrocytes and normalized the protein composition of released erythroid vesicles ( Figure 3D ). Mitapivat significantly reduced the amount of band 3 and membrane associated peroxiredoxin-2 ( Figure 3D ) in the released vesicles, which constitute the protein machinery involved in generation of erythroid vesicles ( 36 , 37 ).…”

“…Flow cytometric analysis of erythroid precursors from BM and spleen from WT and 4.2 –/– mice was carried out using the CD44-Ter119-Fsc hi gating strategy ( 17 ). Total bilirubin and LDH levels were evaluated using standard biochemical assays, as previously reported ( 37 ). The concentration of mouse EPO in plasma was determined using the Mouse Erythropoietin Quantikine ELISA Kit (R&D Systems), following the manufacturer instructions.…”

“…Following staining, cells were fixed, permeabilized, and counterlabeled with anti–Ter-119 FITC (BioLegend) to measure macrophage intracellular fluorescence associated with phagocytosed RBCs. Cells stained as described above without permeabilization served as negative controls of intracellular staining, as previously reported ( 37 ). Anti–80 PerCP-Cy5.5 (BioLegend) was used to determine surface expression of phagocytic receptors on spleen and lung macrophages identified using an anti–F4/80 PE-Cy7 Ab.…”