| Autor: |
Simona Maria Di Modica, Emanuele Tanzi, Violante Olivari, Maria Rosa Lidonnici, Mariateresa Pettinato, Alessia Pagani, Francesca Tiboni, Valeria Furiosi, Laura Silvestri, Giuliana Ferrari, Stefano Rivella, Antonella Nai |
| Přispěvatelé: |
Di Modica, Simona Maria, Tanzi, Emanuele, Olivari, Violante, Lidonnici, Maria Rosa, Pettinato, Mariateresa, Pagani, Alessia, Tiboni, Francesca, Furiosi, Valeria, Silvestri, Laura, Ferrari, Giuliana, Rivella, Stefano, Nai, Antonella |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Popis: |
beta-thalassemia is a genetic disorder caused by mutations in the beta-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications. Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with iron-restricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbb(th1/th2) murine model of TDT. This effect is associated with a decrease in the expression of alpha-globin, which partially corrects the unbalance with beta-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbb(th1/th2) animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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