Background
Myelodysplastic Syndromes (MDS) are characterised by ineffective erythropoiesis, which suppresses liver hepcidin production, leading to unrestrained intestinal iron absorption. Iron overload has increasingly been recognised as a significant factor in MDS. Hepcidin, the primary regulator of iron metabolism, is synthesised by hepatocytes in response to elevated iron levels and inflammation but is negatively regulated by the transmembrane protease serine 6 (TMPRSS6) through the cleavage of hemojuvelin (HJV), a co-receptor in the BMP-SMAD signalling pathway. Inhibiting TMPRSS6 expression offers a promising therapeutic approach to enhance hepcidin production, thereby ameliorating anaemia and iron overload in MDS.
Methods
In this study, we explored the liver-specific delivery of an optimised N-acetylgalactosamine (GalNAc)-conjugated siRNA targeting Tmprss6 (SLN124) in MDS (NHD13) mice. The GalNAc ligand is a well-established liver-targeting moiety due to its high affinity for the asialoglycoprotein receptor (ASGPR). NHD13 and wild-type mice received monthly subcutaneous injections of SLN124 siRNA (3 mg/kg) or the oral iron chelator deferiprone in drinking water (1.25 mg/ml). Pyroptosis was measured by staining for ASC foci and NLRP3, key components of inflammasome activation. NETosis was measured by staining for myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit), characterised by the expulsion of chromatin during cell death.
Results
We found that the degree of iron overload, defined by presence of haemosiderin aggregates in mice, positively correlated with the formation of NETosis and pyroptosis in the bone marrow and spleen of NHD13 mice. MDS mice undergoing iron restriction therapy with SLN124 or DFP, showed altered iron distribution and a significant reduction in both pyroptosis and NETosis formation. Overall, SLN124, which targets Tmprss6 expression, had the greatest impact on inflammatory responses. As a result, long-term SLN124 treatment led to a reduction in ineffective erythropoiesis and extended the lifespan of MDS mice, with 30% surviving up to 450 days, compared to 400 days in control and deferiprone-treated groups.
Conclusion
These findings underscore the potential of SLN124 to reduce iron accumulation and inflammation, potentially slowing disease progression in MDS. They also emphasise the need for further research into the pathological effects of iron toxicity and inflammation in managing MDS.