# Model selection in preclinical nucleic acid therapeutics research

## TL;DR

This paper reviews preclinical models for nucleic acid therapeutics, focusing on how to best assess their effectiveness in early research stages.

## Contribution

The paper provides a critical evaluation and guidance on selecting appropriate preclinical models for nucleic acid therapeutics.

## Key findings

- Current in vitro and in vivo models for nucleic acid therapeutics are reviewed for their efficacy in predicting therapeutic outcomes.
- The paper highlights the importance of choosing the right model systems to ensure meaningful preclinical results.
- It suggests future directions for improving model systems in nucleic acid therapeutic development.

## 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.

This Review examines experimental models for evaluating nucleic acid therapeutics, emphasizing the need for effective preclinical models to assess molecular and phenotypic efficacy at each stage of development.