Model selection in preclinical nucleic acid therapeutics research.

Area of Science:

• Biotechnology
• Pharmacology
• Molecular Biology

Background:

• Nucleic acid therapeutics (NATs) represent a rapidly advancing drug class with increasing clinical trials and market approvals.
• Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are key NAT modalities.
• A significant challenge in NAT development is identifying suitable preclinical models for efficacy assessment.

Purpose of the Study:

• To review and critically evaluate current preclinical efficacy study approaches for ASOs and siRNAs.
• To address key questions regarding the selection and application of in vitro and in vivo models for NAT research.
• To explore future advancements in preclinical modeling for NATs.

Main Methods:

• Literature review and critical analysis of existing preclinical models for NAT efficacy.
• Discussion of strategies for target locus manipulation (surrogate vs. humanization) in preclinical studies.
• Evaluation of the utility of human-derived cells versus surrogate models.

Main Results:

• Current preclinical models for NATs vary in their ability to predict molecular and phenotypic efficacy.
• The choice between surrogate and humanized models depends on the specific NAT and research question.
• Standardized approaches for NAT preclinical testing are still evolving.

Conclusions:

• Optimizing preclinical model selection is essential for the successful development of ASOs and siRNAs.
• Further research is needed to refine and validate preclinical models for NATs.
• Advancements in preclinical modeling will accelerate the translation of NATs to the clinic.