Improved iron parameters due to the iron-restrictive effect of Tmprss6-ASO. Administration of Tmprss6-ASO (with or without overexpression of Epo) to thalassemic animals resulted in significant increase in serum HAMP concentration (A). This was associated with reduced serum iron (B) and transferrin saturation (C) when compared with control animals and animals receiving only fibroblasts overexpressing Epo. Also, liver iron was reduced in a subset of animals (D). Reduction in erythroid iron intake also resulted in a remarkable decrease in ⍺ precipitates on the RBC membrane (E), as corroborated by quantification of the relative abundance of the ⍺ and β globin chains (ImageStudio Lite software) (F). Reduction in ⍺ precipitates induced by Tmprss6-ASO resulted in significant improvement of RBC distribution width (RDW) (G) and normalization of the lifespan of peripheral erythroid cells of treated animals compared with controls (H). Dotted red line indicates mean values for untreated WT mice. Dashed black lines indicates mean values for untreated Hbb^th3/+ mice. Bars represent SD. Asterisks refer to statistically significant differences (****P ≤ .001; ***P ≤ .005; **P ≤ .01; *P ≤ .05). ST, standard.