Immunogenicity Risk Assessment for Nucleic Acid Therapeutics: A Comprehensive Evaluation for ASO, siRNA, and...

The emergence of nucleic acid (NA) therapeutics, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), which are usually delivered directly, and messenger RNAs (mRNAs), which are typically encapsulated in lipid nanoparticles (LNPs), marks a transformative era in precision medicine. While these therapies offer precise approaches for gene regulation or expression, they can trigger unwanted innate and/or adaptive immune responses that can either have no significant impact or adversely affect treatment efficacy and/or patient safety. Consequently, therapies where an adaptive immune response is desired, such mRNA/LNP-based vaccines against infectious diseases or cancer are out of scope of this article. In the present work, the Innovation and Quality Consortium Nucleic Acids Immunogenicity Working Group examines how the various components of NA-based therapies might contribute to their immunogenic potential and describes risk mitigation strategies through product design adaptations during early development stages. In addition, a comprehensive immunogenicity risk assessment framework is described, allowing to effectively define a tailored clinical testing strategy for different NA modalities with varying immunogenicity (IG) consequences. A streamlined monitoring strategy is recommended when minimal impact is expected, whereas extensive testing is suggested when safety concerns arise. Overall, these recommendations ensure that safe and effective NA-based therapies reach patients with an appropriate assessment of the IG potential.