Conjugates are defined single chemical entities with fully modified siRNA conjugated to targeting ligand to help them find their way to a specific cell or tissue within the body. Conjugates are a “lock and key” system, where the lock is the receptor found on the target cell and the key is the ligand attached to the siRNA.
We leverage two conjugate approaches to enable targeted delivery to the liver and the central nervous system (CNS)—GalNAc conjugates and CNS-targeted siRNA conjugates.
GalNAc conjugates – GalNAc, or N-acetylgalactosamine, is a sugar molecule that can recognize and bind to a cell surface protein, the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on liver cells (hepatocytes). The binding affinity to the receptor increases exponentially if several GalNAc units are combined into a multivalent ligand. Our GalNAc-conjugated siRNAs are trivalent, meaning that three GalNAc molecules are clustered and conjugated to one siRNA molecule. This setup guarantees high affinity (strength) of the interaction between ASGPR and the GalNAc ligand, thus promoting optimal efficiency of siRNA delivery to the liver.
RNAi therapeutics utilizing GalNAc conjugate technology are administered subcutaneously. Our medicines GIVLAARI® (givosiran), OXLUMO® (lumasiran), AMVUTTRA® (vutrisiran), and Leqvio® (inclisiran)* utilize GalNAc conjugate delivery.
C16 conjugates – The 2’-O-hexadecyl (C16) is a short lipid chain attached to siRNA that provides lipophilicity to interact with cell membrane or membrane proteins for uptake in multiple cell types, including the cells of the central nervous system (CNS), the lung and eye.
ALN-APP, our investigational RNAi therapeutic targeting amyloid precursor protein in Phase 1 development (in collaboration with Regeneron Pharmaceuticals) for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy, utilizes C16 conjugate technology. ALN-APP is administered intrathecally (via an injection into the spinal cord).
*Licensed to Novartis