Considerations for alternative nonclinical toxicology models for the development of oligonucleotide-based therapeutics
Nucleic Acid Insights 2026; 3(8), 487–495
DOI: 10.18609/nai.2026.060
Small interfering RNA therapeutics have emerged as a transformative class of oligonucleotide-based therapeutics, with multiple approved products and an expanding clinical pipeline targeting diverse disease areas. Because the nonhuman primate is often the only pharmacologically relevant species for these compounds, alternative nonclinical models are increasingly important for developmental and reproductive toxicity and carcinogenicity assessments. This article reviews considerations for selecting nonclinical toxicology models for siRNA-based therapeutics, set against an evolving regulatory landscape shaped by PMDA, FDA, and emerging ICH S13 guidance. Case studies are presented to illustrate points of consideration for using a rodent surrogate in DART or carcinogenicity assessments. Key takeaways emphasize early model qualification, robust historical control data, and strategic use of wild type groups to distinguish on-target from off-target effects.