Novel Iron Chelators Alleviate Symptoms of Thalassemia.

Abstract

Thalassemia is a blood disorder requiring lifelong transfusions for survival. Erythrocytes accumulate toxic iron at their membranes, triggering an oxidative cascade that leads to their premature destruction. We hypothesized that removing this proximate iron compartment as a primary treatment using novel iron chelators, could prevent cell death and alleviate the need for transfusion. Novel, highly cell permeable iron chelators, pyridoxal isonicotinoyl hydrazone and pyridoxal ortho-chlorobenzoyl hydrazone (o-108) were compared to the present mainstay, desferrioxamine and deferiprone, in vitro and in vivo. Treatment of human model b-thalassemic erythrocytes with chelators resulted in significant depletion of membrane-associated iron (P < 0.002) and reduced oxidative stress, as indicated by methemoglobin levels (P < 0.01). When administered to β-thalassemic mice, iron chelators mobilized erythrocyte membrane iron (P < 0.05), reduced cellular oxidation (P < 0.03), and prolonged erythrocyte survival. Consistently, these mice showed substantial correction of hematological abnormalities (P < 0.05). A beneficial effect as early as the erythroid precursor stage, was also determined by normalized proportions of mature versus immature reticulocytes (P < 0.05). Remarkably, all four compounds reduced iron accumulation in target organs (P < 0.05). Most importantly, o-108 revealed superior activity compared to desferrioxamine, further decreasing iron in spleen and liver by ~2-fold and ~5-fold, respectively (P < 0.05). Our study demonstrates that iron chelators ameliorate thalassemia in a human and murine model, and validates their primary use as an alternative to transfusion therapy.