Abstract Accurate assessment of tissue distribution for oligonucleotide therapeutic (ONT) drug candidates is essential for understanding pharmacokinetic behavior and predicting therapeutic efficacy. ONTs present a unique challenge with their rapid systemic clearance coupled with prolonged tissue retention, making comprehensive tissue concentration evaluation critical for successful drug development. The IQ Consortium Tissue Concentration Working Group surveyed member companies about their current tissue concentration assessment methods to understand industry practices and identify areas for improvement. Most companies reported that ONTs still represent a relatively small portion of their pre-candidate selection portfolios, reflecting the evolving nature of this therapeutic modality. siRNAs dominated development efforts across surveyed organizations, followed by antisense oligonucleotides, indicating clear therapeutic class preferences within the industry. Assessment strategies varied considerably across organizations, highlighting different approaches to resource allocation and risk management. While some companies routinely evaluate tissue concentrations for all ONT programs regardless of indication or target, others take a more selective, program-dependent approach based on compound characteristics and therapeutic objectives. Despite this strategic variability, there was universal reliance on LC–MS for quantification, often supplemented with qPCR/RT-qPCR and hybridization assays for comprehensive analytical coverage. All surveyed companies integrate tissue concentration data into translational pharmacokinetic modeling efforts, yet few have adopted physiologically-based pharmacokinetic (PBPK) models as standard practice. Companies recognize the value of improving ONT tissue distribution assessment through standardized methodology tailored to specific oligonucleotide classes. Graphical Abstract
McCoy et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: