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Related Experiment Video

Updated: Jun 13, 2026

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Assessing Hybridization-Dependent Off-Target Risk for Therapeutic Oligonucleotides: Updated Industry Recommendations.

Patrik Andersson1, Sebastien A Burel2, Heather Estrella3

  • 1AstraZeneca R&D, Gothenburg, Sweden.

Nucleic Acid Therapeutics
|February 6, 2025
PubMed
Summary
This summary is machine-generated.

Updated guidelines address oligonucleotide therapeutics (ONTs) safety by detailing a five-step framework to identify, assess, and manage hybridization-dependent off-target effects, crucial for clinical trial progression.

Keywords:
ASOhybridization-dependentin silico predictionoff-targetproductive uptakerisk assessmentsiRNAtherapeutic oligonucleotides

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Safety

Background:

  • Off-target effects (OffT) from oligonucleotide therapeutics (ONTs) binding unintended RNA are a safety concern.
  • Current OffT assessment guidelines are limited, with recent updates from Japan (2020) and the US FDA (2022).
  • Technological advancements necessitate updated industry recommendations for robust OffT evaluation.

Purpose of the Study:

  • To present updated industry recommendations for assessing OffT in oligonucleotide therapeutics (ONTs).
  • To establish a comprehensive five-step framework for OffT identification, verification, risk assessment, and management.
  • To provide guidance for various ONT classes, considering factors like chemistry and delivery.

Main Methods:

  • Developed a five-step workflow: in silico prediction/transcriptomics, relevant cell type focus, in vitro verification/margin assessment, risk assessment, and OffT management.
  • Incorporated expertise from a new Oligonucleotide Safety Working Group (OSWG) subcommittee.
  • Considered ONT-specific factors (chemistry, delivery, tissue distribution) and machine learning for enhanced prediction.

Main Results:

  • A comprehensive framework for OffT assessment in ONTs is proposed.
  • Detailed considerations are provided for different ONT classes and their specific evaluation needs.
  • Strategies for experimental verification, risk assessment, and management of unavoidable OffTs are discussed.

Conclusions:

  • Updated recommendations aim to enhance the safety profile of ONTs in clinical trials.
  • The proposed framework will aid in managing unavoidable OffTs and inform regulatory guidance.
  • These recommendations serve as a valuable resource for ONT development and regulatory harmonization.