TL;DR: Introduction Mechanisms of Antisense Drug Action, an Introduction, S.A. Levin, R.Z. Yu, and R.S. Geary Routes and Formulations for Delivery ofAntisense Oligonucleotides, G.E. Hardee, L.G. Tillman, and T.T. Maraganore.
Abstract: Basic Principles of Antisense Technology Stanley T. Crooke Medicinal Chemistry of Antisense Oligonucleotides P. Dan Cook Analytical Methods for Antisense Drugs Janet M. Leeds and Lendell L. Cummins A Role for Antisense Technology in the Discovery of Highly Specific and Versatile Signal Transduction Inhibitors Brett P. Monia, Erich Koller, and William A. Gaarde Methods of Selecting Sites in RNA for Antisense Targeting Susan M. Freier Properties of Phosphorothioate Oligonucleotides Pharmacokinetic Properties in Animals Richard S. Geary, Rosie Z. Yu, Janet M. Leeds, Michael V. Templin, Tanya A. Watanabe, Scott P. Henry, and Arthur A. Levin Suborgan Pharmacokinetics Rosanne M. Crooke and Mark J. Graham Pharmacokinetic Properties in Humans Rosie Z. Yu, Steven L. Schoenfeld, Richard S. Geary, Tanya A. Watanabe, and Arthur A. Levin Toxicity of Antisense Oligonucleotides Arthur A. Levin, Scott P. Henry, David Monteith, and Michael V. Templin Clinical Safety of Phosphorothioate Oligodeoxynucleotides F. Andrew Dorr, Josephine M. Glover, and T. Jesse Kwoh General Pharmacology of Phosphorothioate Oligodeoxynucleotides C. Frank Bennett Properties of Advanced Novel Clinical Classes of Oligonucleotides Pharmacology of 2'-0-(2-Methoxy)ethyl Modified Antisense Oligonucleotides Nicholas M. Dean, Madeline Butler, Brett P. Monia, and Muthiah Manoharan Locked Nucleic Acid Jesper Wengel Antisense Properties of Peptide Nucleic Acid (PNA) Uffe Koppelhus and Peter J. Nielsen Phosphorodiamidate Morpholino Oligomers Patrick Iversen Oligonucleotide Conjugates in Antisense Technology Muthiah Manoharan Immune Stimulation by Oligonucleotides Arthur M. Krieg Pre-mRNA Splicing as a Target for Antisense Oligonucleotides Ryszard Kole and Danielle Mercatante Application of Antisense Oligonucleotides to the Study of CNS Protein Function Siew Peng Ho Antisense Approach to Isoform-Specific Blockade of Acetylcholinesterase Hermona E. Soreq and Shlomo Seidman Serine/Threonine Protein Phosphates Richard E. Honkanen Pharmacological Activities of Antisense Drugs: Inflammatory Diseases James G. Karras, Kathleen J. Myers, and Brenda F. Baker Respirable Antisense Oligonucleotides (RASONs) Jonathan W. Nyce Combined Antisense Therapy and Chemotherapy in Animal Models Dan Mercola Antisense Oligodesoxynucleotide Strategies in Renal and Cardiovascular Disease Hermann Haller, Christian Maasch, Duska Dragun, Maren Wellner, and Friedrich C. Luft The Development of Antisense Oligonucleotides as Antivirals Lisa R. Grillone Clinical Activities in Patients with Solid Tumors or Lymphoma Jon T. Holmlund Nucleic Acid Therapeutics for the Treatment of Human Leukemia Alan M. Gewirtz ISIS 2302, an Antisense Inhibitor of Intercellular Adhesion Molecule 1 (ICAM-1) William R. Shanahan, Jr. New Routes and Novel Formulations for Delivery of Antisense Oligonucleotides Gregory E. Hardee, Susan P. Weinbach, and Lloyd G. Tillman DNA-Binding Molecules Roland W. Burli and Heinz E. Moser Targeted Genome Modification via Triple Helix Formation Margaret A. Macris and Peter M. Glazer Intracellular Ribozyme Applications John J. Rossi
TL;DR: Comprehensive genomic analysis of the important human pathogen Staphylococcus aureus was achieved by a strategy involving antisense technology in a regulatable gene expression system and allowed gene function to be characterized in a comprehensive, defined set of conditionally growth-defective/lethal isogenic strains.
Abstract: Comprehensive genomic analysis of the important human pathogen Staphylococcus aureus was achieved by a strategy involving antisense technology in a regulatable gene expression system. In addition to known essential genes, many genes of unknown or poorly defined biological function were identified. This methodology allowed gene function to be characterized in a comprehensive, defined set of conditionally growth-defective/lethal isogenic strains. Quantitative titration of the conditional growth effect was performed either in bacterial culture or in an animal model of infection. This genomic strategy offers an approach to the identification of staphylococcal gene products that could serve as targets for antibiotic discovery.
TL;DR: The 2'-position of the carbohydrate moiety has proven to be a fertile position for oligonucleotide modifications for antisense technology and the 2'-modifications exhibit high binding affinity to target RNA, enhanced chemical stability and nuclease resistance and increased lipophilicity.
TL;DR: High-affinity next-generation antisense oligonucleotides are used, which have higher potency than previous generations and can be systemically administered without a lipid vehicle, for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically.
Abstract: Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 dose-escalation study.
TL;DR: This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.
Abstract: Recent studies have led to a greater appreciation of the diverse roles RNAs play in maintaining normal cellular function and how they contribute to disease pathology, broadening the number of potential therapeutic targets. Antisense oligonucleotides are the most direct means to target RNA in a selective manner and have become an established platform technology for drug discovery. There are multiple molecular mechanisms by which antisense oligonucleotides can be used to modulate RNAs in cells, including promoting the degradation of the targeted RNA or modulating RNA function without degradation. Antisense drugs utilizing various antisense mechanisms are demonstrating therapeutic potential for the treatment of a broad variety of diseases. This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.