TMPRSS6 INHIBITION IMPROVES BONE HEALTH IN B-THALASSEMIA MICE

Beta-thalassemia is a genetic disorder arising from mutations in the ß-globin gene, leading to ineffective erythropoiesis and iron overload contributing to liver fibrosis, cardiac toxicities and osteoporosis. The bone marrow expansion and iron overload, due to ineffective erythropoiesis, are the main drivers of reduced bone quality. To target the iron overload, we generated a monoclonal antibody (REGN7999) inhibiting TMPRSS6, a negative regulator of hepcidin, the main iron homeostasis regulating hormone. In the Hbb^th3/+ mouse model of ß-thalassemia, REGN7999 treatment reduced liver and serum iron and improved red blood cell health. Oxidative stress and senescence of red blood cells was reduced resulting in reduced red blood cell turnover and more effective erythropoiesis in ß-thalassemia mice.  Using µCT, we tested if bone quality improves in response to TMPRSS6 inhibition, as erythropoiesis is now more effective and iron loading reduced. We found that bone mineral density and bone mineral content in ß-thalassemia mice were restored to wildtype levels after 8 weeks of REGN7999 treatment. Taken together, these data suggest that improving red blood cell health and reducing iron loading reverses the ß-thalassemia associated osteoporosis. This effect can potentially improve the quality of life of ß-thalassemia patients.