Immunogenicity risk assessment of novel modalities using new approach methodologies.

A forward-looking NAM framework is proposed to adapt mathematically modeled, AI, organ-on-a-chip, and advanced in vitro/ex vivo tools for predicting immunogenicity risks of gene therapies, cell treatments, and gene editors.

• Why it matters: Unwanted immune responses limit clinical success of novel modalities and can undermine both safety and efficacy, while regulators seek scientifically validated new approach methodologies to reduce animal testing.
• What they did: The Perspective critically evaluates how the current NAM toolkit—originally built for protein therapeutics—could be adapted to address risks from transgene products, delivery vehicles, and gene-editing machinery, including pre-existing immunity and repeat dosing barriers.
• The result: It outlines a framework for developing and validating next-generation predictive immunogenicity tools, supporting robust long-term monitoring strategies to safely unlock therapeutic potential.

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