title: OSWG Recommendations for Genotoxicity Testing of Novel Oligonucleotide-Based Therapeutics.
abstract: The Oligonucleotide Safety Working Group subcommittee on genotoxicity testing considers therapeutic oligonucleotides (ONs) unlikely to be genotoxic based on their properties and on the negative results for ONs tested to date. Nonetheless, the subcommittee believes that genotoxicity testing of new ONs is warranted because modified monomers could be liberated from a metabolized ON and incorporated into DNA and could hypothetically cause chain termination, miscoding, and/or faulty replication or repair. The standard test battery as described in Option 1 of International Conference on Harmonisation S2(R1) is generally adequate to assess such potential. However, for the in vitro assay for gene mutations, mammalian cells are considered more relevant than bacteria for most ONs due to their known responsiveness to nucleosides and their greater potential for ON uptake; on the other hand, bacterial assays may be more appropriate for ONs containing non-ON components. Testing is not recommended for ONs with only naturally occurring chemistries or for ONs with chemistries for which there is documented lack of genotoxicity in systems with demonstrated cellular uptake. Testing is recommended for ONs that contain non-natural chemical modifications and use of the complete drug product (including linkers, conjugates, and liposomes) is suggested to provide the most clinically relevant assessment. Documentation of uptake into cells comparable to those used for genotoxicity testing is proposed because intracellular exposure cannot be assumed for these large molecules. ONs could also hypothetically cause mutations through triple helix formation with genomic DNA and no tests are available for detection of such sequence-specific mutations across the entire genome. However, because the potential for triplex formation by therapeutic ONs is extremely low, this potential can be assessed adequately by sequence analysis.
authors.affiliation: 1 Berman Consulting , Wayland, Massachusetts.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Berman
authors.affiliation: 2 Alnylam Pharmaceuticals , Cambridge, Massachusetts.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Barros
authors.affiliation: 3 Merck Research Laboratories , West Point, Pennsylvania.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Galloway
authors.affiliation: 4 Federal Institute for Drugs and Medical Devices (BfArM) , Bonn, Germany .
authors.forename: Peter
authors.initials: P
authors.lastname: Kasper
authors.affiliation: 5 Consultant , Concord, Massachusetts.
authors.forename: Frederick B
authors.initials: FB
authors.lastname: Oleson
authors.affiliation: 6 AstraZeneca , Innovative Medicines & Early Development, Cambridge, United Kingdom .
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Priestley
authors.affiliation: 7 Forensic and National Security Sciences Institute, Syracuse University , Syracuse, New York.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Sweder
authors.affiliation: 8 MSR Pharma Services, Inc. , Lincolnshire, Illinois.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schlosser
authors.affiliation: 9 Pfizer, Inc. , Groton, Connecticut.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Sobol
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009152:Mutagenicity Tests; D009841:Oligonucleotides / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D009841:Oligonucleotides