Therapeutic RNA agents that act through the RNA interference (RNAi) pathway are specific and potent inhibitors of gene expression. Chemically synthesized versions of these inhibitors are called short interfering RNAs (siRNAs). These agents may be designed to target disease pathways previously considered �non-druggable�. Recently, systemic delivery of RNAi therapeutics to liver hepatocytes by subcutaneous administration has been achieved at Alnylam Pharmaceuticals using GalNAc-siRNA conjugate delivery platform. In this approach, the siRNAs are conjugated with multivalent N-acetylgalactosamine (GalNAc) residues that are recognized by the asialoglycoprotein receptor (ASGPR). ASGPR is a C-type lectin receptor expressed on human hepatocyte cell surfaces at 0.5 to 1 million copies per cell. ASGPR recognizes an exposed terminal galactose to mediate clearance of serum glycoproteins via clathrin-mediated endocytosis. Recognition by the ASGPR requires multi-valency with appropriate spatial distribution and orientation of the GalNAc residues. Binding affinities of these trivalent ligands are in low nM range. GalNAc-siRNA conjugates are active in numerous animal models and hold significant promise for targeting disease-causing genes produced in liver. Alnylam is advancing several GalNAc-siRNA conjugates through pre-clinical and clinical development to address genetically defined diseases with significant unmet medical need. Recent advances with the GalNAc-siRNA conjugate platform will be presented using several disease targets.

Carbohydrate conjugates for systemic delivery of RNAi therapeutics

248th National Meeting (2014)

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