Correcting β-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity

Carla Casu, Mariateresa Pettinato, Alison Liu, Mariam Aghajan, Vania Lo Presti, Maria Rosa Lidonnici, Kevin A. Munoz, Emir O'Hara, Violante Olivari, Simona Maria Di Modica, Sheri Booten, Shuling Guo, Garry Neil, Reem Miari, Nir Shapir, Inbal Zafir-Lavie, Hagit Domev, Giuliana Ferrari, Despina Sitara, Antonella NaiStefano Rivella

Research output: Contribution to journalArticlepeer-review


β-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by β-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in β-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in β-thalassemia and could provide guidance to translate some of these approaches into viable therapies.

Original languageEnglish (US)
Pages (from-to)1968-1979
Number of pages12
Issue number17
StatePublished - Oct 22 2020


  • Animals
  • Cells, Cultured
  • Erythropoiesis/drug effects
  • Erythropoietin/administration & dosage
  • Gene Expression Regulation/drug effects
  • Genetic Therapy/methods
  • Iron/metabolism
  • Iron Overload/genetics
  • Male
  • Membrane Proteins/antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotides, Antisense/administration & dosage
  • Receptors, Transferrin/genetics
  • Serine Endopeptidases/genetics
  • beta-Thalassemia/metabolism

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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