Project description

Myelodysplastic Syndromes (MDS) are characterised by ineffective erythropoiesis, which suppresses the production of hepcidin in the liver, leading to unchecked intestinal iron absorption. Iron overload is a major contributor to oxidative stress and inflammatory responses, which in turn drive various pathological conditions. Moreover, cells exposed to excess iron show dysplastic changes, with elevated levels of intracellular reactive oxygen species (ROS), decreased expression of anti-apoptotic genes, and DNA damage. Understanding the cause-and-effect relationship of iron overload could lead to the development of innovative therapeutic strategies to delay or prevent disease progression.

Hepcidin, the central regulator of iron metabolism, is produced by hepatocytes in response to elevated iron levels and inflammation. However, its production is negatively regulated by transmembrane protease serine 6 (TMPRSS6), which cleaves hemojuvelin (HJV), a co-receptor in the BMP-SMAD signalling pathway. Inhibiting TMPRSS6 expression thus presents a promising therapeutic strategy to enhance hepcidin production, reducing iron overload and inflammation.

Recent advances in understanding the biology of TMPRSS6 and its mechanisms of action have led to the development of novel therapeutic approaches for patients with iron overload disorders. In MDS mice treated with siRNA targeting TMPRSS6 (GalNAc-siTmprss6), we observed altered iron biodistribution and reduced inflammation, which significantly extended their survival. These findings support our hypothesis that iron dysregulation is a maladaptive response associated with pro-inflammatory signalling in the bone marrow microenvironment during the early stages of the disease.

The proposed research aims to deepen our understanding of the mechanisms underlying aberrant immune functions in MDS and provide new insights into disease progression. Targeting dysregulated inflammation, particularly in LR-MDS patients, holds potential as a therapeutic strategy. Positive outcomes from this research could pave the way for improved treatment options for LR-MDS and similar disorders.