Definition

An RNA interference (RNAi) therapeutic composed of the liver-targeted ligand N-acetylgalactosamine (GalNAc) conjugated to small-interfering RNAs (siRNAs) directed against the serine protease TMPRSS6, that may potentially be used in the treatment of iron overload associated with certain disorders such as beta thalassemia and myelodysplastic syndromes. Upon administration of TMPRSS6 RNAi SLN124, the GalNAc moiety targets and binds with high affinity to asialoglycoprotein receptors (ASGPRs) expressed on hepatocytes. Once inside the cell, the siRNAs bind to and silence TMPRSS6 mRNA and inhibit both the translation and expression of the TMPRSS6 protein. This prevents TMPRSS6-mediated suppression of the bone morphogenetic protein (BMP)‐SMAD signaling pathway and leads to an increase in hepcidin levels. Hepcidin decreases the uptake of dietary iron and the release of iron from cellular storage, which may normalize iron levels. Hepcidin plays a key role in the homeostasis of systemic iron; low levels of hepcidin are associated with iron overload in certain disorders.