Coordinated by GU Ventures
Webinar: February 19, 15:00 – 16:30
PULSE Challenge: Properties and challenges with therapeutic oligonucleotides illustrated by hybridization-dependent off-target assessment
Registration and more information
Presenter:
Dr Patrik Andersson, PhD
Senior Director, RNA Therapeutics Safety
AstraZeneca, Gothenburg, Sweden
Abstract:
Hybridization-dependent off-target (OffT) effects, occurring when oligonucleotides bind via Watson-Crick-Franklin hybridization to unintended RNA transcripts, remain a critical safety concern for therapeutic oligonucleotides (ONTs). Despite the importance of OffT assessment of clinical trial ONT candidates, formal guidelines were for many years lacking, with only brief mentions in Japanese regulatory documents (2020) and FDA recommendations for HBV (hepatitis B virus) treatments (2022). A subcommittee of the Oligonucleotide Safety Working Group (OSWG), was formed to gather experiences and develop updated industry recommendations for assessing OffTs of ONTs. The proposed workflow encompasses five key steps: 1) OffT identification through in silico complementarity prediction and transcriptomics analysis, 2) focus on cell types with relevant ONT activity, 3) in vitro verification and margin assessment, 4) risk assessment based on the OffT biological role, and 5) management of unavoidable OffTs.
This presentation will describe this workflow and discuss considerations for various ONT classes, emphasizing the importance of ONT-specific factors such as chemistry, delivery systems, and tissue distribution in OffT evaluation. It will also cover strategies for experimental verification and risk assessment and discuss the potential of machine learning models to enhance OffT prediction.
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