Contributions
Abstract: EP1057
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Polycythaemia Vera (PV) is a myeloproliferative neoplasm (MPN) in which overproduction of mature red cells renders patients at increased risk of serious thrombotic events. First line therapy includes periodical venesection (blood withdrawal) to reduce haematocrit, and thus risk of thrombosis, and induces whole body iron deficiency, which suppresses further red cell production. However, resulting systemic iron deficiency and fluid shifts lead to unwanted side effects including vaso-vagal complications, fatigue and cognitive dysfunction. Therefore, venesection is often poorly tolerated.
Hepcidin, the liver-derived hormone that regulates systemic iron homeostasis, is normally suppressed in iron deficiency (via decreased BMP/SMAD signalling) or by increased erythropoiesis (via increased erythroferrone expression) but is increased by inflammation (via IL6- STAT3 signalling). Interestingly, hepcidin levels are not suppressed in PV despite sustained increased erythropoiesis and iron deficiency, suggesting relative upregulation in this disease context.
Aims
We hypothesised that further upregulation of hepcidin in PV limits iron available for erythropoiesis. This would prevent patients from obtaining the high red cell counts that are incompatible with life. We aimed to discover whether therapeutically increasing endogenous hepcidin expression in PV through knock-down of its regulator, Tmprss6, could act as a therapeutic phlebotomy and decrease disease severity.
Methods
We developed a novel bone marrow transplant model of PV driven by the mutant human JAK2V617F allele. PV and control mice were subcutaneously administered anti-Tmprss6 siRNA or a non-targeting control siRNA once every 3 weeks for 3 doses. Mice were humanely euthanised and organs collected for downstream analysis.
Results
PV mice had comparable levels of hepcidin mRNA and protein as control mice, recapitulating what has previously been observed in patients. Mice administered anti-Tmprss6 siRNA showed ablated Tmprss6 gene expression which resulted in sustained increase of endogenous hepatic hepcidin mRNA and serum protein levels, compared to mice given non-targeting siRNA. Increased serum hepcidin significantly decreased serum iron levels but did not cause iron deficiency in peripheral organs, as determined by liver iron content. PV animals administered anti-Tmprss6 siRNA had significantly lower haematocrit (45.9 vs 61.2%; P<0.0001), haemoglobin levels (12.0 vs 17.7g/dL; P<0.0001) and mean cell volume (36.1 vs 48.4fL, P<0.0001) than PV animals treated with control siRNA.
Conclusion
These data provide pre-clinical evidence that increasing endogenous hepcidin expression via anti-Tmprss6 RNAi could be a viable therapeutic avenue for treatment of PV. This treatment approach does not affect fluid levels and may reduce risk of systemic iron deficiency, the two concerns with conventional first line therapy. A related siRNA compound targeting TMPRSS6, SLN124, is in clinical development for hepcidin deficient anaemias. The inherent long-lasting duration of action coupled with patient friendly route of administration could provide benefit by decreasing the requirement for venesection and increasing comfort for patients with PV.
Keyword(s): Hepcidin, Iron, Myeloproliferative disorder, Polycythemia vera
Abstract: EP1057
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Polycythaemia Vera (PV) is a myeloproliferative neoplasm (MPN) in which overproduction of mature red cells renders patients at increased risk of serious thrombotic events. First line therapy includes periodical venesection (blood withdrawal) to reduce haematocrit, and thus risk of thrombosis, and induces whole body iron deficiency, which suppresses further red cell production. However, resulting systemic iron deficiency and fluid shifts lead to unwanted side effects including vaso-vagal complications, fatigue and cognitive dysfunction. Therefore, venesection is often poorly tolerated.
Hepcidin, the liver-derived hormone that regulates systemic iron homeostasis, is normally suppressed in iron deficiency (via decreased BMP/SMAD signalling) or by increased erythropoiesis (via increased erythroferrone expression) but is increased by inflammation (via IL6- STAT3 signalling). Interestingly, hepcidin levels are not suppressed in PV despite sustained increased erythropoiesis and iron deficiency, suggesting relative upregulation in this disease context.
Aims
We hypothesised that further upregulation of hepcidin in PV limits iron available for erythropoiesis. This would prevent patients from obtaining the high red cell counts that are incompatible with life. We aimed to discover whether therapeutically increasing endogenous hepcidin expression in PV through knock-down of its regulator, Tmprss6, could act as a therapeutic phlebotomy and decrease disease severity.
Methods
We developed a novel bone marrow transplant model of PV driven by the mutant human JAK2V617F allele. PV and control mice were subcutaneously administered anti-Tmprss6 siRNA or a non-targeting control siRNA once every 3 weeks for 3 doses. Mice were humanely euthanised and organs collected for downstream analysis.
Results
PV mice had comparable levels of hepcidin mRNA and protein as control mice, recapitulating what has previously been observed in patients. Mice administered anti-Tmprss6 siRNA showed ablated Tmprss6 gene expression which resulted in sustained increase of endogenous hepatic hepcidin mRNA and serum protein levels, compared to mice given non-targeting siRNA. Increased serum hepcidin significantly decreased serum iron levels but did not cause iron deficiency in peripheral organs, as determined by liver iron content. PV animals administered anti-Tmprss6 siRNA had significantly lower haematocrit (45.9 vs 61.2%; P<0.0001), haemoglobin levels (12.0 vs 17.7g/dL; P<0.0001) and mean cell volume (36.1 vs 48.4fL, P<0.0001) than PV animals treated with control siRNA.
Conclusion
These data provide pre-clinical evidence that increasing endogenous hepcidin expression via anti-Tmprss6 RNAi could be a viable therapeutic avenue for treatment of PV. This treatment approach does not affect fluid levels and may reduce risk of systemic iron deficiency, the two concerns with conventional first line therapy. A related siRNA compound targeting TMPRSS6, SLN124, is in clinical development for hepcidin deficient anaemias. The inherent long-lasting duration of action coupled with patient friendly route of administration could provide benefit by decreasing the requirement for venesection and increasing comfort for patients with PV.
Keyword(s): Hepcidin, Iron, Myeloproliferative disorder, Polycythemia vera