What question did this study set out to answer?

The aim is to evaluate the selection of preclinical models for nucleic acid therapeutics to ensure effective evaluation of their efficacy.

February 11, 2026Open Access

Model selection in preclinical nucleic acid therapeutics research

Puntos clave

The aim is to evaluate the selection of preclinical models for nucleic acid therapeutics to ensure effective evaluation of their efficacy.
Introduced various preclinical models used for nucleic acid therapeutics such as ASOs and siRNAs.
Critiqued current methodologies for assessing molecular activity and phenotypic outcomes in NAT studies.
Discussed the appropriateness of using surrogate or human-derived targets.
Identified key challenges in selecting effective in vitro models for NAT activity assessment.
Outlined appropriate scenarios for using human-derived cells based on the study phase.
Emphasized the need for ongoing evaluation and adaptation in preclinical efficacy studies.

Resumen

Abstract Nucleic acid therapeutics (NATs) are a maturing drug class with many active clinical trials and a growing number of approvals. For NATs such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), a major hurdle during the research and development phase lies in selecting preclinical model systems with meaningful readouts on molecular and phenotypic efficacy. Key questions include: Which in vitro models are best positioned to quantify NAT activity and identify hits? In advancing a NAT from in vitro to in vivo studies, when is it appropriate to employ a surrogate or humanize a target locus; conversely, when is it appropriate to rely solely on human-derived cells? In this review, we will introduce and critique current approaches to ASO and siRNA preclinical efficacy studies and consider future advances in this fast-moving therapeutic area.

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