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      Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

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          Abstract

          A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.

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          Most cited references 89

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          MicroRNA biogenesis: coordinated cropping and dicing.

           V Kim (2005)
          The recent discovery of microRNAs (miRNAs) took many by surprise because of their unorthodox features and widespread functions. These tiny, approximately 22-nucleotide, RNAs control several pathways including developmental timing, haematopoiesis, organogenesis, apoptosis, cell proliferation and possibly even tumorigenesis. Among the most pressing questions regarding this unusual class of regulatory miRNA-encoding genes is how miRNAs are produced in cells and how the genes themselves are controlled by various regulatory networks.
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            Endosomal escape pathways for delivery of biologicals.

            Despite continuous improvements in delivery systems, the development of methods for efficient and specific delivery of targeted therapeutic agents still remains an issue in biological treatments such as protein and gene therapy. The endocytic pathway is the major uptake mechanism of cells and any biological agents, such as DNA, siRNA and proteins. These agents become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving an effective biological based therapy is to facilitate the endosomal escape and ensure cytosolic delivery of the therapeutics. Bacteria and viruses are pathogens which use different mechanisms to penetrate the membranes of their target cells and escape the endosomal pathway. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effect of protonable groups and fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape. Several viral and bacterial proteins have been identified that are involved in this process. In addition, chemical agents and photochemical methods to rupture the endosomal membrane have been described. New synthetic biomimetic peptides and polymers with high efficacy in facilitating the endosomal escape, low pathogenicity and toxicity have been developed. Each strategy has different characteristics and challenges for designing the best agents and techniques to facilitate the endosomal escape are ongoing. In this review, several mechanisms and agents which are involved in endosomal escape are introduced. Copyright © 2010 Elsevier B.V. All rights reserved.
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              Endocytic mechanisms for targeted drug delivery.

              Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway has serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer's disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.
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                Author and article information

                Contributors
                Journal
                Mol Ther Nucleic Acids
                Mol Ther Nucleic Acids
                Molecular Therapy. Nucleic Acids
                American Society of Gene & Cell Therapy
                2162-2531
                10 December 2016
                17 March 2017
                10 December 2016
                : 6
                : 116-132
                Affiliations
                [1 ]Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
                [2 ]Institute of Molecular Medicine, Peking University, Beijing 100871, China
                Author notes
                []Corresponding author: Yuanyu Huang, Advanced Research Institute for Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China. yyhuang@ 123456pku.edu.cn
                Article
                S2162-2531(16)30371-7
                10.1016/j.omtn.2016.12.003
                5363494
                28325278
                de800b68-28e4-471a-bd1a-6a810f7c683f
                © 2016 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Review

                Molecular medicine

                galnac, sirna, anti-mir, aso, liver-targeted delivery, asgpr, oligonucleotide, rnai

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