Targeting TMPRSS6 with SLN124: A Novel GalNAc-siRNA Approach to Iron Overload and Erythropoietic Dysfunction in Beta-Thalassemia

Excess iron accumulation can result in organ damage, leading to severe health issues such as liver cirrhosis, diabetes, stunted growth, and heart failure. Conditions like beta-thalassemia, myelodysplastic syndrome, and hereditary hemochromatosis are particularly at risk due to iron overload. Beta-thalassemia major patients experience this due to frequent blood transfusions, while those with beta thalassemia intermedia develop it through excessive iron absorption in the gastrointestinal tract, stemming from inefficient erythropoiesis. A crucial factor in iron regulation, the peptide hormone hepcidin, is often found at abnormally low levels, failing to inhibit intestinal iron absorption mediated by ferroportin. In hereditary hemochromatosis, genetic mutations in the hepcidin-ferroportin pathway lead to excessive liver iron. Hepcidin is primarily produced in the liver and is regulated by the BMP/SMAD signaling pathway, with its expression negatively controlled by the TMPRSS6 gene-encoded matriptase-2.

RNA interference offers a potent method for silencing genes linked to diseases. Silence Therapeutics has harnessed this through the development of siRNA conjugate technology, targeting liver-specific gene expression. The company's GalNAc-conjugated siRNAs effectively bind to hepatocyte-expressed asialoglycoprotein receptors, providing a targeted and safe delivery system for therapeutic applications.

Our research presents the pharmacological profile of SLN124, a GalNAc-siRNA conjugate designed to target TMPRSS6. A single subcutaneous dose of this compound has shown significant modulation of gene expression in mice and primates over an extended period. SLN124 has been shown to lower systemic iron levels, transferrin saturation, and tissue iron levels in a rodent model of hereditary hemochromatosis type 1. Moreover, it has demonstrated therapeutic efficacy in reducing iron overload in mice, both as a standalone treatment and in combination with oral iron chelators. The impact of these treatments on red blood cell parameters and tissue iron levels will be detailed. We also report on the therapeutic effects of SLN124 in a beta-thalassemia intermedia model, highlighting its dose-dependent and sustained influence on gene expression, iron storage modulation, and the normalization of erythropoiesis and anemia. Preclinical safety and tolerability studies indicate that SLN124 is well-tolerated, positioning it as a promising treatment for iron-loading anemias such as beta-thalassemia. The compound is in preclinical development, with plans for human trials in 2019 targeting beta-thalassemia and myelodysplastic syndrome patients.