Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions

Abstract

β-thalassemia is an inherited anemia characterized by ineffective erythropoiesis. Blood transfusions are required for survival in transfusion-dependent β-thalassemia and are also occasionally needed in patients with non-transfusion-dependent β-thalassemia. Patients with transfusion-dependent β-thalassemia often have elevated transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI) levels, which can lead to organ iron overload, oxidative stress, and vascular damage. Vamifeport is an oral ferroportin inhibitor that was previously shown to ameliorate anemia, ineffective erythropoiesis, and dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia, under non-transfused conditions. Our study aimed to assess the effects of oral vamifeport on iron-related parameters (including plasma NTBI levels) and ineffective erythropoiesis following blood transfusions in Hbbth3/+ mice. A single dose of vamifeport prevented the transient transfusion-mediated NTBI increase in Hbbth3/+ mice. Compared with vehicle treatment, vamifeport significantly increased hemoglobin levels and red blood cell counts in transfused mice. Vamifeport treatment also significantly improved ineffective erythropoiesis in the spleens of Hbbth3/+ mice, with additive effects observed when treatment was combined with repeated transfusions. Vamifeport corrected leukocyte counts and significantly improved iron-related parameters (serum transferrin, TSAT and erythropoietin levels) versus vehicle treatment in Hbbth3/+ mice, irrespective of transfusion status. In summary, vamifeport prevented transfusion-mediated NTBI formation in Hbbth3/+ mice. When given alone or combined with blood transfusions, vamifeport also ameliorated anemia, ineffective erythropoiesis, and dysregulated iron homeostasis. Administering vamifeport together with repeated blood transfusions additively ameliorated anemia and ineffective erythropoiesis in this mouse model, providing preclinical proof-of-concept for the efficacy of combining vamifeport with blood transfusions in β-thalassemia.

A randomized placebo−controlled clinical trial of oral green tea epigallocatechin 3−gallate on erythropoiesis and oxidative stress in transfusion−dependent β−thalassemia patients

“…Therapeutic hepcidin mimetics (e.g., rusfertide) and hepcidin agonists (e.g., TMPRSS6 inhibitor and mini−hepcidin PR73 and mHS17) aim to reverse iron deficiency by targeting hepcidin−ferroportin axis, increase iron influx, mobilize tissue iron, and consequently normalize hematological parameters ( Chua et al, 2015 ; Makis et al, 2021 ; Handa et al, 2023 ). Furthermore, oral ferroportin inhibitors (e.g., vamifeport and substituted benzoimidazole compounds) can relieve ineffective erythropoiesis and improve body iron parameters in iron overload−associated TDT mice, as well as treat patients suffering from neurodegenerative and cardiac diseases ( Kadam et al, 2021 ; Kalleda et al, 2023 ). Previous studies have revealed that polyphenols dose dependently inhibit RBC hemolysis induced by AAPH, possibly by membrane anti-lipid peroxidation and protein antioxidation; EGCG and ECG had higher antioxidant capacity, while EGC and EC showed more effective ROS-radical scavenging activity ( Zhang et al, 1997 ; Zou et al, 2001 ).…”