Contributions
Abstract: EP1204
Type: E-Poster Presentation
Session title: Sickle cell disease
Background
In sickle cell disease (SCD) a point mutation in the β-globin gene leads to synthesis of sickle hemoglobin (HbS) in erythrocytes. Upon deoxygenation in capillary blood vessels, HbS polymerizes in rigid fibers causing red blood cell (RBC) membrane distortion, intravascular hemolysis, increased endothelial adhesion and inflammation that might lead to vaso-occlusion (VO) and painful crisis. The kinetics of HbS polymerization is strongly dependent on the intracellular HbS concentration and a relatively small reduction of the cellular HbS concentration might prevent HbS polymerization and its sequelae. Clinical cases showed that iron deficiency in SCD patients decreases the mean corpuscular HbS concentration, intravascular hemolysis and pain crisis. A recent publication using the Townes mouse model of SCD showed that dietary iron restriction in juvenile mice (3 weeks old), fed low iron diet (LID) immediately after weaning, improved hemolysis, hematological and endothelial cell activation markers. Despite the promising effect in the mouse model, dietary iron restriction is not readily implemented in a compliant way for SCD patients. We have previously shown that iron restriction by inhibition of ferroportin, the unique iron transporter in mammals, reduced hemolysis, improved hemodynamics and prevented VO events in the Townes model of SCD.
Aims
To compare the effects of pharmacological iron restriction by the oral ferroportin inhibitor VIT-2763 to dietary iron restriction induced by low iron diet (LID) in adult Townes mice.
Methods
Townes mice (7 weeks old) engineered to synthesise exclusively human HbS were orally administered either the ferroportin inhibitor VIT-2763 (60 mg/kg bidaily) or vehicle for 6 weeks and received dietary iron corresponding to standard rodent diet (250 ppm iron). Dietary iron restriction was achieved by feeding Townes mice LID (10 ppm iron) for 6 weeks. Hematological parameters, hemolysis and vascular and systemic inflammation markers were evaluated at the study end.
Results
RBCs of Townes mice treated with VIT-2763, but not mice fed LID, showed hematological parameters indicating iron-restricted erythropoiesis: reductions in mean corpuscular volume (MCV), mean corpuscular Hb (MCH) and reticulocyte Hb content, whereas percentages of hypochromic and microcytic RBCs were increased with preserved RBC counts. Importantly, the intracellular HbS concentration, as measured by the corpuscular Hb concentration mean (CHCM) was significantly reduced in Townes mice receiving VIT-2763, but not in mice fed LID. In agreement with the determining effect of HbS concentration on intravascular hemolysis, mice treated with VIT-2763, but not mice fed LID, showed lower markers of intravascular hemolysis and endothelial dysfunction. Iron restriction by VIT-2763 but not via LID decreased blood leukocyte counts and circulating chemokines such as CCL5, suggesting the potential of VIT-2763 to reduce systemic inflammation in Townes mice. Iron restriction via LID, but not by VIT-2763, increased significantly erythropoietin (EPO) plasma levels, suggesting a feedback response to iron deficiency, which might further stimulate erythropoiesis.
Conclusion
This data demonstrated that VIT-2763 induced iron-restricted erythropoiesis and reduced vascular and systemic inflammation in adult Townes mice. The differential effects of VIT-2763 and LID in adult Townes mice highlight the role of systemic ferroportin inhibition for efficient iron restriction and therapeutic benefit.
Keyword(s): Iron metabolism, Sickle cell anemia, Sickle cell disease
Abstract: EP1204
Type: E-Poster Presentation
Session title: Sickle cell disease
Background
In sickle cell disease (SCD) a point mutation in the β-globin gene leads to synthesis of sickle hemoglobin (HbS) in erythrocytes. Upon deoxygenation in capillary blood vessels, HbS polymerizes in rigid fibers causing red blood cell (RBC) membrane distortion, intravascular hemolysis, increased endothelial adhesion and inflammation that might lead to vaso-occlusion (VO) and painful crisis. The kinetics of HbS polymerization is strongly dependent on the intracellular HbS concentration and a relatively small reduction of the cellular HbS concentration might prevent HbS polymerization and its sequelae. Clinical cases showed that iron deficiency in SCD patients decreases the mean corpuscular HbS concentration, intravascular hemolysis and pain crisis. A recent publication using the Townes mouse model of SCD showed that dietary iron restriction in juvenile mice (3 weeks old), fed low iron diet (LID) immediately after weaning, improved hemolysis, hematological and endothelial cell activation markers. Despite the promising effect in the mouse model, dietary iron restriction is not readily implemented in a compliant way for SCD patients. We have previously shown that iron restriction by inhibition of ferroportin, the unique iron transporter in mammals, reduced hemolysis, improved hemodynamics and prevented VO events in the Townes model of SCD.
Aims
To compare the effects of pharmacological iron restriction by the oral ferroportin inhibitor VIT-2763 to dietary iron restriction induced by low iron diet (LID) in adult Townes mice.
Methods
Townes mice (7 weeks old) engineered to synthesise exclusively human HbS were orally administered either the ferroportin inhibitor VIT-2763 (60 mg/kg bidaily) or vehicle for 6 weeks and received dietary iron corresponding to standard rodent diet (250 ppm iron). Dietary iron restriction was achieved by feeding Townes mice LID (10 ppm iron) for 6 weeks. Hematological parameters, hemolysis and vascular and systemic inflammation markers were evaluated at the study end.
Results
RBCs of Townes mice treated with VIT-2763, but not mice fed LID, showed hematological parameters indicating iron-restricted erythropoiesis: reductions in mean corpuscular volume (MCV), mean corpuscular Hb (MCH) and reticulocyte Hb content, whereas percentages of hypochromic and microcytic RBCs were increased with preserved RBC counts. Importantly, the intracellular HbS concentration, as measured by the corpuscular Hb concentration mean (CHCM) was significantly reduced in Townes mice receiving VIT-2763, but not in mice fed LID. In agreement with the determining effect of HbS concentration on intravascular hemolysis, mice treated with VIT-2763, but not mice fed LID, showed lower markers of intravascular hemolysis and endothelial dysfunction. Iron restriction by VIT-2763 but not via LID decreased blood leukocyte counts and circulating chemokines such as CCL5, suggesting the potential of VIT-2763 to reduce systemic inflammation in Townes mice. Iron restriction via LID, but not by VIT-2763, increased significantly erythropoietin (EPO) plasma levels, suggesting a feedback response to iron deficiency, which might further stimulate erythropoiesis.
Conclusion
This data demonstrated that VIT-2763 induced iron-restricted erythropoiesis and reduced vascular and systemic inflammation in adult Townes mice. The differential effects of VIT-2763 and LID in adult Townes mice highlight the role of systemic ferroportin inhibition for efficient iron restriction and therapeutic benefit.
Keyword(s): Iron metabolism, Sickle cell anemia, Sickle cell disease