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782 The Oral Ferroportin Inhibitor VIT-2763 Prevents Hemolysis and Vaso-Occlusion in a Sickle Cell Disease Model

Program: Oral and Poster Abstracts
Session: 113. Hemoglobinopathies, Excluding Thalassemia—New Genetic Approaches to Sickle Cell Disease: Poster I
Hematology Disease Topics & Pathways:
sickle cell disease, Diseases, Hemoglobinopathies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Rahima Zennadi, PhD1, Naja Nyffenegger, PhD2*, Anna Flace2*, Natarajaswamy Kalleda, PhD2*, Cédric Doucerain2*, Giada Ingoglia, PhD2*, Franz Dürrenberger, PhD2* and Vania Manolova, Ph.D2*

1Medicine, Duke University School of Medicine, Durham, NC
2Vifor (International) Ltd., St. Gallen, Switzerland

Background: Intravascular hemolysis of sickle red blood cells (sRBCs) is a hallmark of sickle cell disease (SCD) that ensues multiple downstream effects resulting in anemia, expansion of erythropoiesis, release of hemoglobin (Hb) and heme, iron overload, increased cell adhesion, inflammation, vaso-occlusion (VO) and organ injury. Curative therapies, such as hematopoietic stem cell transplantation or gene therapy are limited to a small patient population or not yet available. Currently approved therapies address some of the pathologies in SCD, however, drugs that target broader sequelae of SCD are needed and prevention of hemolysis might provide a novel therapeutic option. Interestingly, overt iron deficiency in patients with SCD has been associated with reduction of sickle Hb (HbS) in sRBCs and decreased markers of hemolysis. We hypothesized that restricting iron by blocking ferroportin, the unique iron transporter in mammals, might reduce hemolysis and thereby improve blood flow and prevent VO events.

Aim: To test the effect of the oral ferroportin inhibitor VIT-2763 on hemolysis, hemodynamics, and prevention of VO in a SCD model.

Methods: Townes mice producing human HbS were treated with the ferroportin inhibitor VIT-2763 for 4 to 6 weeks. Hematological parameters, hemolysis and vascular inflammation markers were evaluated at the study end. To assess the effect of VIT-2763 on hemodynamics, acute VO was triggered by injecting Townes mice with TNF alpha. Hemodynamics and blood cell adhesion to microvasculature was investigated using intravital microscopy.

Results: Mice receiving VIT-2763 showed reduced hemolysis markers, such as plasma lactate dehydrogenase, bilirubin and heme. The RBC indices of Townes mice treated with VIT-2763 showed changes attributable to iron restricted erythropoiesis: decrease in the corpuscular Hb concentration mean (CHCM), mean corpuscular volume (MCV), increased percentage of hypochromic and microcytic RBCs. In addition, RBCs of Townes mice treated with VIT-2763 showed lower levels of the apoptosis marker phosphatidylserine. Notably, VIT-2763 reduced the spleen size of Townes mice, indicating amelioration of extramedullary erythropoiesis and clearance of sRBCs. Unexpectedly, treatment with VIT-2763 lowered significantly blood leukocyte counts, particularly neutrophils, suggesting the potential of VIT-2763 to reduce inflammation in this SCD model.

Interaction of sRBCs, activated leukocytes and free heme with endothelium causes vascular inflammation and promotes VO and organ injury. Endothelial dysfunction in SCD is associated with increased levels of soluble adhesion molecules, such as sVCAM-1. VIT-2763 decreased sVCAM-1 levels in Townes mice, suggesting lowered vascular inflammation.

Intravital video microscopy of fluorescently labeled blood cells in the microvasculature of control sickle mice showed marked vascular adhesion of RBCs and leukocytes. Cell adhesion in inflamed venules of the vehicle group was persistent, resulting in complete blood stasis in approximately 30% of the total microvessels recorded. Importantly, the number of adherent cells in mice treated with VIT-2763 was reduced by about 70% compared to the vehicle group. Strikingly, all of the microvessels from Townes mice treated with VIT-2763 showed normal blood flow.

Conclusions: Iron restriction by the oral ferroportin inhibitor VIT-2763 has the potential to alleviate VO events and thereby improve hemodynamics in the SCD model, presumably by reducing sickle Hb in RBCs, hemolysis and vascular inflammation.

Disclosures: Zennadi: GlycoMimetics: Research Funding. Nyffenegger: Vifor (International) Ltd: Current Employment. Flace: Vifor (International) Ltd: Current Employment. Kalleda: Vifor (International) Ltd: Current Employment. Doucerain: Vifor (International) Ltd: Current Employment. Ingoglia: Vifor (International) Ltd: Current Employment. Dürrenberger: Vifor (International) Ltd: Current Employment. Manolova: Vifor (International) Ltd: Current Employment.

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