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RNAi‐mediated reduction of hepatic Tmprss6 diminishes anemia and secondary iron overload in a splenectomized mouse model of β‐thalassemia intermedia
- Source :
- American Journal of Hematology. 93:745-750
- Publication Year :
- 2018
- Publisher :
- Wiley, 2018.
-
Abstract
- Diminished β-globin synthesis in β-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β-thalassemia to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia. To interrogate the efficacy of RNAi-mediated reduction of Tmprss6 in splenectomized β-thalassemia, splenectomized β-thalassemic Hbbth3/+ animals were treated with a GalNAc-conjugated siRNA targeting Tmprss6 (GalNAc-Tmprss6) and their hematological and iron parameters monitored. We demonstrate that treatment with GalNAc-Tmprss6 significantly diminishes Tmprss6 expression and appropriately elevates hepcidin expression in splenectomized Hbbth3/+ animals. Similar to unsplenectomized animals, treated animals have markedly improved anemia due to diminished ineffective erythropoiesis and reduced iron loading in both serum and tissue. These results suggest that RNAi-mediated reduction of Tmprss6 may have positive outcomes even in splenectomized β-thalassemia patients.
- Subjects :
- 0301 basic medicine
Ineffective erythropoiesis
congenital, hereditary, and neonatal diseases and abnormalities
TMPRSS6
medicine.medical_specialty
Acetylgalactosamine
Iron Overload
Anemia
Thalassemia
medicine.disease_cause
Mice
03 medical and health sciences
0302 clinical medicine
Hepcidins
Hepcidin
hemic and lymphatic diseases
Internal medicine
medicine
Animals
Erythropoiesis
biology
business.industry
Serine Endopeptidases
beta-Thalassemia
Membrane Proteins
Hematology
medicine.disease
Hemolysis
Disease Models, Animal
030104 developmental biology
Endocrinology
Liver
Splenectomy
biology.protein
RNA Interference
business
030215 immunology
Hormone
Subjects
Details
- ISSN :
- 10968652 and 03618609
- Volume :
- 93
- Database :
- OpenAIRE
- Journal :
- American Journal of Hematology
- Accession number :
- edsair.doi.dedup.....dad40cb9ca899f06fb3d0b4b78ef66fc