Definition

An antisense oligonucleotide (ASO) targeting the transmembrane protease serine 6 (TMPRSS6) mRNA and conjugated to the liver-targeted ligand N-acetylgalactosamine (GalNAc), that can potentially be used to regulate TMPRSS6, hepcidin and iron levels and treat iron overload and anemia associated with certain disorders such as beta thalassemia and myelodysplastic syndromes. Upon subcutaneous administration of sapablursen, the GalNAc moiety targets and binds with high affinity to asialoglycoprotein receptors (ASGPRs) expressed on hepatocytes. Once inside the cell, the ASO blocks the translation of the TMPRSS6 protein. Reduction of the TMPRSS6 level 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 reduces serum iron, normalizes iron levels and stimulates erythropoiesis. Hepcidin plays a key role in the homeostasis of systemic iron; low levels of hepcidin are associated with iron overload in certain diseases, such as beta-thalassemia and polycythemia vera. TMPRSS6 negatively regulates hepcidin expression and plays a key role in iron homeostasis.