Journal Article

GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics

Dowdy, Steven F., Springer, Aaron D.

2018

Overview

Short-interfering RNA (siRNA)-induced RNAi responses have great potential to treat a wide variety of human diseases from cancer to pandemic viral outbreaks to Parkinson's Disease. However, before siRNAs can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading RNAs on the outside cells from getting to the inside of cells. Not surprisingly, significant effort has been placed in developing a wide array of delivery technologies. Foremost of these has been the development of N -acetylgalactosamine (GalNAc) siRNA conjugates for delivery to liver. Tris-GalNAc binds to the Asialoglycoprotein receptor that is highly expressed on hepatocytes resulting in rapid endocytosis. While the exact mechanism of escape across the endosomal lipid bilayer membrane remains unknown, sufficient amounts of siRNAs enter the cytoplasm to induce robust, target selective RNAi responses in vivo . Multiple GalNAc-siRNA conjugate clinical trials, including two phase III trials, are currently underway by three biotech companies to treat a wide variety of diseases. GalNAc-siRNA conjugates are a simple solution to the siRNA delivery problem for liver hepatocytes and have shown the RNAi (and antisense oligonucleotide) field the path forward for targeting other tissue types.

• Publisher: Mary Ann Liebert, Inc,SAGE Publications
• Subject: Acetylgalactosamine - metabolism / Acids / Antisense oligonucleotides / Antisense RNA / Asialoglycoprotein Receptor - genetics / Asialoglycoprotein Receptor - metabolism / Cancer / Clinical trials / Clinical Trials as Topic / Conjugates / Cytoplasm / Endocytosis / Endosomes - chemistry / Endosomes - metabolism / Gene expression / Gene Transfer Techniques / Glycoconjugates - metabolism / Hepatitis / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Hepatocytes - virology / Investments / Ligands / Liver / Liver - metabolism / Liver - pathology / Liver - virology / Medical research / Movement disorders / N-Acetylgalactosamine / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - chemistry / Nanoparticles - metabolism / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - pathology / Neoplasms - therapy / Neurodegenerative diseases / Outbreaks / Pandemics / Parkinson Disease - genetics / Parkinson Disease - metabolism / Parkinson Disease - pathology / Parkinson Disease - therapy / Parkinson's disease / Reviews / Ribonucleic acid / RNA / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / RNA-mediated interference / siRNA / Studies / Virus Diseases - genetics / Virus Diseases - metabolism / Virus Diseases - pathology / Virus Diseases - therapy