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Beta-thalassemia is one of the most frequently inherited disorders caused by mutations in the beta globin gene or its promoter, leading to reduced or absent beta globin synthesis. Ineffective erythropoiesis (IE) and consequent extramedullary hematopoiesis, splenomegaly and systemic iron overload are major features of this disease. The disease course can be associated with severe anemia and need for lifelong transfusion therapy (thalassemia major, TM) or relatively less severe anemia (non-transfusion-dependent thalassemia, NTDT, or thalassemia inter-media, TI). Patients affected by beta-thalassemia intermedia do not require chronic blood transfusions for survival. However, transfusion-independence is still associated with a variety of serious clinical morbidities.1–3 In NTDT the master regulator of iron homeostasis, hepcidin (Hamp), is chronically repressed.4–7 Therefore, patients absorb abnormally high levels of iron, requiring iron chelation to prevent the clinical sequelae associated with iron overload. Iron homeostasis needs to be carefully regulated in order to avoid toxicity due to its excess. If untreated, iron overload leads to organ failure and death. For this reason, in beta-thalassemia and other iron-related disorders, the management of iron overload has become the main focus. Chelation therapy, however, does not target the mechanism responsible for abnormal iron absorption, which is low levels of Hamp expression and synthesis. It has been shown that in mice affected by NTDT (Hbbth3/+ or th3/+), second generation antisense oligonucleotides (Tmprss6-ASO) or lipid nanoparticle (LNP)-formulated siRNAs can reduce the expression of transmembrane serine protease Tmprss6, one of the major suppressors of hepcidin expression.8,9 Suppression of Tmprss6 led to an increase in hepcidin synthesis and hemoglobin levels. These observations were also associated with a net reduction in splenomegaly, iron overload, transferrin saturation (TfSat), formation of insoluble membrane-bound globins (hemichromes) and reactive oxygen species (ROS).9 Thus, we hypothesized that the simultaneous use of the iron chelator deferiprone (DFP) with Tmprss6-ASO (Tmprss6-ASO+DFP) could combine the positive effects of Tmprss6-ASO on erythropoiesis and iron absorption with the chelation benefit on organ iron content. In this study, 3- to 4-month-old Hbbth3/+ females were treated with 50 mg/kg of Tmprss6 antisense oligonucleotide (Tmprss6-ASO, twice a week for 6 weeks) or Tmprss6-ASO in combination with the oral iron chelator DFP dissolved in the drinking water at 1.25 mg/ml, using either a commercial diet (normally used in the facility where animals were housed) containing 200 ppm of iron, or a physiological diet containing 35 ppm of iron. The majority of the animals available were treated using the commercial diet and just a few animals per group received the physiological one. With both diets we obtained the same trend in behavior, but considering that the numbers were not comparable, we decided to show only the data obtained from the 200 ppm diet.

haematologica

Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia