Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides

Acute Neurotoxicity of Antisense Oligonucleotides After Intracerebroventricular Injection Into Mouse Brain Can Be Predicted from Sequence Features

(2022) Peter H. Hagedorn et al.   Nucleic Acid Therapeutics

Partial restoration of brain dystrophin and behavioral deficits by exon skipping in the muscular dystrophy X‐linked ( mdx ) mouse

(2022) Faouzi Zarrouki et al.   ANNALS OF NEUROLOGY

Phase-In to Phase-Out—Targeted, Inclusive Strategies Are Needed to Enable Full Replacement of Animal Use in the European Union

(2022) Lindsay J. Marshall et al.   Animals

Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

(2022) Sarah J Tabrizi et al.   LANCET NEUROLOGY

Early-Stage Identification and Avoidance of Antisense Oligonucleotides Causing Species-Specific Inflammatory Responses in Human Volunteer Peripheral Blood Mononuclear Cells

(2022) Sebastien A. Burel et al.   Nucleic Acid Therapeutics

Considerations of the Japanese Research Working Group for the ICH S6 & Related Issues Regarding Nonclinical Safety Assessments of Oligonucleotide Therapeutics: Comparison with Those of Biopharmaceuticals

(2021) Yoko Hirabayashi et al.   Nucleic Acid Therapeutics

Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of plateletleukocyte aggregates

(2021) Martina H. Lundberg Slingsby et al.   HAEMATOLOGICA

Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

(2021) Guillermo Vasquez et al.   NUCLEIC ACIDS RESEARCH

Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip

(2021) Tom T. G. Nieskens et al.   ARCHIVES OF TOXICOLOGY

Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4

(2021) Tomasz Z. Tomkiewicz et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome

(2021) Eric William Ottesen et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

eSkip-Finder: a machine learning-based web application and database to identify the optimal sequences of antisense oligonucleotides for exon skipping

(2021) Shuntaro Chiba et al.   NUCLEIC ACIDS RESEARCH

Sequence-dependent inhibition of cGAS and TLR9 DNA sensing by 2′-O-methyl gapmer oligonucleotides

(2021) Roxane Valentin et al.   NUCLEIC ACIDS RESEARCH

Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides

(2021) Brooke A Anderson et al.   NUCLEIC ACIDS RESEARCH

Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides

(2021) Erle M. Holgersen et al.   Nucleic Acid Therapeutics

Evaluation of Phosphorus and Non-Phosphorus Neutral Oligonucleotide Backbones for Enhancing Therapeutic Index of Gapmer Antisense Oligonucleotides

(2021) Guillermo Vasquez et al.   Nucleic Acid Therapeutics

Likelihood of Nonspecific Activity of Gapmer Antisense Oligonucleotides Is Associated with Relative Hybridization Free Energy

(2020) Andrew T. Watt et al.   Nucleic Acid Therapeutics

Refining LNA safety profile by controlling phosphorothioate stereochemistry

(2020) Erik Daa Funder et al.   PLoS One

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

(2020) Kian Huat Lim et al.   Nature Communications

Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates

(2020) Christopher R Brown et al.   NUCLEIC ACIDS RESEARCH

Urinary Kidney Biomarker Panel Detects Preclinical Antisense Oligonucleotide-Induced Tubular Toxicity

(2020) Åsa Sandelius et al.   TOXICOLOGIC PATHOLOGY

Applicability of hiPSC-derived neuronal co-cultures and rodent primary cortical cultures for in vitro seizure liability assessment

(2020) Anke M Tukker et al.   TOXICOLOGICAL SCIENCES

Outcomes of the European Federation of Pharmaceutical Industries and Associations Oligonucleotide Working Group Survey on Nonclinical Practices and Regulatory Expectations for Therapeutic Oligonucleotide Safety Assessment

(2020) Yann Tessier et al.   Nucleic Acid Therapeutics

Using RNA-seq to Assess Off-Target Effects of Antisense Oligonucleotides in Human Cell Lines

(2020) Sven Michel et al.   Molecular Diagnosis & Therapy

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

(2020) Paymaan Jafar-nejad et al.   NUCLEIC ACIDS RESEARCH

Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index

(2019) Wen Shen et al.   NATURE BIOTECHNOLOGY

Evaluating the Impact of Variable Phosphorothioate Content in Tricyclo-DNA Antisense Oligonucleotides in a Duchenne Muscular Dystrophy Mouse Model

(2019) Lucía Echevarría et al.   Nucleic Acid Therapeutics

Intrarenal Renin–Angiotensin System Involvement in the Pathogenesis of Chronic Progressive Nephropathy—Bridging the Informational Gap Between Disciplines

(2019) Leslie A. Obert et al.   TOXICOLOGIC PATHOLOGY

The Pharmacokinetics of 2′-O-Methyl Phosphorothioate Antisense Oligonucleotides: Experiences from Developing Exon Skipping Therapies for Duchenne Muscular Dystrophy

(2019) Sieto Bosgra et al.   Nucleic Acid Therapeutics

Evaluation of off‐target effects of gapmer antisense oligonucleotides using human cells

(2019) Tokuyuki Yoshida et al.   GENES TO CELLS

Hybridization-mediated off-target effects of splice-switching antisense oligonucleotides

(2019) Juergen Scharner et al.   NUCLEIC ACIDS RESEARCH

Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy

(2019) Philippine Aupy et al.   Molecular Therapy-Nucleic Acids

Reversal of siRNA-mediated gene silencing in vivo

(2018) Ivan Zlatev et al.   NATURE BIOTECHNOLOGY

Principles for targeting RNA with drug-like small molecules

(2018) Katherine Deigan Warner et al.   NATURE REVIEWS DRUG DISCOVERY

Acute hepatotoxicity of 2′ fluoro-modified 5–10–5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins

(2018) Wen Shen et al.   NUCLEIC ACIDS RESEARCH

Investigation into the Mechanism(s) That Leads to Platelet Decreases in Cynomolgus Monkeys During Administration of ISIS 104838, a 2ʹ-MOE-Modified Antisense Oligonucleotide

(2018) Padmakumar Narayanan et al.   TOXICOLOGICAL SCIENCES

Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity

(2018) Maja M. Janas et al.   Nature Communications

Intracerebroventricular Administration of a 2′-O-Methyl Phosphorothioate Antisense Oligonucleotide Results in Activation of the Innate Immune System in Mouse Brain

(2018) Lodewijk J.A. Toonen et al.   Nucleic Acid Therapeutics

A Sensitive In Vitro Approach to Assess the Hybridization-Dependent Toxic Potential of High Affinity Gapmer Oligonucleotides

(2018) Andreas Dieckmann et al.   Molecular Therapy-Nucleic Acids

The Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies

(2018) Maja M. Janas et al.   TOXICOLOGIC PATHOLOGY

The Oligonucleotide Safety Working Group (OSWG)

(2018) Dave Schubert et al.   Nucleic Acid Therapeutics

Clinical Expert Panel on Monitoring Potential Lung Toxicity of Inhaled Oligonucleotides: Consensus Points and Recommendations

(2018) Eric W. Alton et al.   Nucleic Acid Therapeutics

GalNAc Conjugation Attenuates the Cytotoxicity of Antisense Oligonucleotide Drugs in Renal Tubular Cells

(2018) Sabine Sewing et al.   Molecular Therapy-Nucleic Acids

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol

(2017) Kausik K. Ray et al.   NEW ENGLAND JOURNAL OF MEDICINE

Managing the sequence-specificity of antisense oligonucleotides in drug discovery

(2017) Peter H. Hagedorn et al.   NUCLEIC ACIDS RESEARCH

Antisense oligonucleotides targeting translation inhibitory elements in 5′ UTRs can selectively increase protein levels

(2017) Xue-hai Liang et al.   NUCLEIC ACIDS RESEARCH

The Distinct and Cooperative Roles of Toll-Like Receptor 9 and Receptor for Advanced Glycation End Products in Modulating In Vivo Inflammatory Responses to Select CpG and Non-CpG Oligonucleotides

(2017) Suzanne Paz et al.   Nucleic Acid Therapeutics

Impurities in Oligonucleotide Drug Substances and Drug Products

(2017) Daniel Capaldi et al.   Nucleic Acid Therapeutics

Recommendations of the Oligonucleotide Safety Working Group's Formulated Oligonucleotide Subcommittee for the Safety Assessment of Formulated Oligonucleotide-Based Therapeutics

(2017) Jennifer L. Marlowe et al.   Nucleic Acid Therapeutics

Assessment of the Effects of 2′-Methoxyethyl Antisense Oligonucleotides on Platelet Count in Cynomolgus Nonhuman Primates

(2017) Scott P. Henry et al.   Nucleic Acid Therapeutics

The Effects of 2′-O-Methoxyethyl Containing Antisense Oligonucleotides on Platelets in Human Clinical Trials

(2017) Stanley T. Crooke et al.   Nucleic Acid Therapeutics

Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice

(2017) Lodewijk J.A. Toonen et al.   Molecular Therapy-Nucleic Acids

Inhibition of EGF Uptake by Nephrotoxic Antisense Drugs In Vitro and Implications for Preclinical Safety Profiling

(2017) Annie Moisan et al.   Molecular Therapy-Nucleic Acids

Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model

(2017) Karima Relizani et al.   Molecular Therapy-Nucleic Acids

Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs

(2017) Piotr J. Kamola et al.   Molecular Therapy-Nucleic Acids

Assessing single-stranded oligonucleotide drug-induced effects in vitro reveals key risk factors for thrombocytopenia

(2017) Sabine Sewing et al.   PLoS One

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

(2016) Béla Z. Schmidt et al.   ARCHIVES OF TOXICOLOGY

Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers

(2016) Stanley T Crooke et al.   MOLECULAR THERAPY

Translation efficiency of mRNAs is increased by antisense oligonucleotides targeting upstream open reading frames

(2016) Xue-hai Liang et al.   NATURE BIOTECHNOLOGY

Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides

(2016) Defne Bayik et al.   PHARMACOLOGICAL RESEARCH

Establishment of a Predictive In Vitro Assay for Assessment of the Hepatotoxic Potential of Oligonucleotide Drugs

(2016) Sabine Sewing et al.   PLoS One

OSWG Recommendations for Genotoxicity Testing of Novel Oligonucleotide-Based Therapeutics

(2016) Cindy L. Berman et al.   Nucleic Acid Therapeutics

Considerations for the Characterization and Interpretation of Results Related to Alternative Complement Activation in Monkeys Associated with Oligonucleotide-Based Therapeutics

(2016) Scott P. Henry et al.   Nucleic Acid Therapeutics

Effects of Repeated Complement Activation Associated with Chronic Treatment of Cynomolgus Monkeys with 2′-O-Methoxyethyl Modified Antisense Oligonucleotide

(2016) Lijiang Shen et al.   Nucleic Acid Therapeutics

Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides

(2015) Richard S. Geary et al.   ADVANCED DRUG DELIVERY REVIEWS

Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial

(2015) Eveline P. van Poelgeest et al.   BRITISH JOURNAL OF CLINICAL PHARMACOLOGY

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

(2015) Ulrike Flierl et al.   JOURNAL OF EXPERIMENTAL MEDICINE

Antisense oligonucleotide–directed inhibition of nonsense-mediated mRNA decay

(2015) Tomoki T Nomakuchi et al.   NATURE BIOTECHNOLOGY

Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages

(2015) Xue-hai Liang et al.   NUCLEIC ACIDS RESEARCH

In silicoandin vitroevaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization

(2015) Piotr J. Kamola et al.   NUCLEIC ACIDS RESEARCH

Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts

(2015) Sebastien A. Burel et al.   NUCLEIC ACIDS RESEARCH

Scientific and Regulatory Policy Committee Points-to-consider Paper*

(2015) Jeffery A. Engelhardt et al.   TOXICOLOGIC PATHOLOGY

Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin

(2015) Jeff R. Crosby et al.   Nucleic Acid Therapeutics

Oligo Safety Working Group Exaggerated Pharmacology Subcommittee Consensus Document

(2015) Doug Kornbrust et al.   Nucleic Acid Therapeutics

Identification of RNA Sequence Motifs Stimulating Sequence-Specific TLR8-Dependent Immune Responses

(2014) A. Forsbach et al.   JOURNAL OF IMMUNOLOGY

Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study

(2014) Thomas Voit et al.   LANCET NEUROLOGY

Sequence motifs associated with hepatotoxicity of locked nucleic acid—modified antisense oligonucleotides

(2014) Andrew D. Burdick et al.   NUCLEIC ACIDS RESEARCH

Comparison of the transcriptional landscapes between human and mouse tissues

(2014) Shin Lin et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Antisense Oligonucleotide Therapies

(2014) Kendall S. Frazier   TOXICOLOGIC PATHOLOGY

Considerations for Assessment of Reproductive and Developmental Toxicity of Oligonucleotide-Based Therapeutics

(2014) Joy Cavagnaro et al.   Nucleic Acid Therapeutics

Recommendations for Safety Pharmacology Evaluations of Oligonucleotide-Based Therapeutics

(2014) Cindy L. Berman et al.   Nucleic Acid Therapeutics

Mechanism of Alternative Complement Pathway Dysregulation by a Phosphorothioate Oligonucleotide in Monkey and Human Serum

(2014) Scott P. Henry et al.   Nucleic Acid Therapeutics

Acute Kidney Injury During Therapy With an Antisense Oligonucleotide Directed Against PCSK9

(2013) Eveline P. van Poelgeest et al.   AMERICAN JOURNAL OF KIDNEY DISEASES

Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk

(2013) Gregory S. Thomas et al.   JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

A Human In Vitro Whole Blood Assay to Predict the Systemic Cytokine Response to Therapeutic Oligonucleotides Including siRNA

(2013) Christoph Coch et al.   PLoS One

Species-specific Inflammatory Responses as a Primary Component for the Development of Glomerular Lesions in Mice and Monkeys Following Chronic Administration of a Second-generation Antisense Oligonucleotide

(2013) Kendall S. Frazier et al.   TOXICOLOGIC PATHOLOGY

Hepatotoxic Potential of Therapeutic Oligonucleotides Can Be Predicted from Their Sequence and Modification Pattern

(2013) Peter H. Hagedorn et al.   Nucleic Acid Therapeutics

Characterization of Target mRNA Reduction Through In Situ RNA Hybridization in Multiple Organ Systems Following Systemic Antisense Treatment in Animals

(2013) Gene Hung et al.   Nucleic Acid Therapeutics

Assessing unintended hybridization-induced biological effects of oligonucleotides

(2012) Morten Lindow et al.   NATURE BIOTECHNOLOGY

Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis

(2012) Holly B. Kordasiewicz et al.   NEURON

Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

(2012) Gordon C. Hard et al.   TOXICOLOGICAL SCIENCES

Repeat-Dose Toxicology Evaluation in Cynomolgus Monkeys of AVI-4658, a Phosphorodiamidate Morpholino Oligomer (PMO) Drug for the Treatment of Duchenne Muscular Dystrophy

(2011) Peter Sazani et al.   INTERNATIONAL JOURNAL OF TOXICOLOGY

Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application

(2009) Aimee L. Jackson et al.   NATURE REVIEWS DRUG DISCOVERY

Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100

(2008) Rosie Z. Yu et al.   BIOCHEMICAL PHARMACOLOGY