Distribution and biotransformation of therapeutic antisense oligonucleotides and conjugates

Drug properties of antisense oligonucleotides (ASOs) differ significantly from those of traditional small-molecule therapeutics. In this review, we focus on ASO disposition, mainly as characterized by distribution and biotransformation, of nonconjugated and conjugated ASOs. We introduce ASO chemistry to allow the following in-depth discussion on bioanalytical methods and determination of distribution and elimination kinetics at low concentrations over extended periods of time. The resulting quantitative data on the parent oligonucleotide, and the identification and quantification of formed metabolites define the disposition. Proper quantitative understanding of disposition is pivotal for nonclinical to clinical predictions, supports communication with health agencies, and increases the probability of delivering optimal ASO therapy to patients.

Automated summary

This review article highlights the significant differences in drug properties between antisense oligonucleotides (ASOs) and traditional small-molecule therapeutics, focusing on the distribution and biotransformation characteristics of nonconjugated and conjugated ASOs. Understanding the disposition of ASOs is crucial for both nonclinical and clinical predictions, as well as for communication with health agencies to optimize ASO therapy for patients.