Initial evaluation of the use of human liver microtissues for the hepatotoxicity assessment of antisense oligonucleotides

About the hepatotoxicity assessment of antisense oligonucleotides

Background and Purpose

Antisense oligonucleotides form a fast-growing class of therapeutic drugs. Still, their current safety assessment process results in a significant fraction of them being stopped late in the development process for hepatotoxicity. Antisense oligonucleotides concentrate in the liver and trigger liver transaminase signals. The specific mechanisms causing liver injury by antisense oligonucleotides include the induction of apoptosis, off-target effects, and the saturation of RNA processing machinery.

Micro-physiological systems are in vitro models that have the potential to, among other methods, improve the safety assessment process of antisense oligonucleotides by detecting hepatotoxicity earlier. The human liver microtissue is one such system and is routinely used by therapeutic drug developers to evaluate the hepatotoxicity of small molecules. However, its relevance for the safety assessment of antisense oligonucleotides has not yet been evaluated. This work evaluates the relevance of human liver microtissues to assess the hepatotoxic potential of antisense oligonucleotides.

Methods

To this aim, antisense oligonucleotides with documented in vivo liver data were tested in human liver microtissues for uptake, efficacy, cytotoxicity, and apoptosis induction. The correlation between their in vitro response and their hepatotoxicity was evaluated.

Results

Antisense oligonucleotides are uniformly taken up by human liver microtissues and downregulate the target messenger ribonucleic acid for up to 14 days. In general, the cytotoxicity and apoptosis induced in human liver microtissues correlate with their documented hepatotoxicity, with cellular adenosinetriphosphate content being the best-performing biomarker.

Conclusions

Altogether, these results suggest that the human liver microtissue is a promising in vitro tool to evaluate the hepatotoxic potential of antisense oligonucleotides. Future investigations should assess more such compounds with documented in vivo liver data for a thorough, statistically robust assessment.

Download InSphero's poster about the hepatotoxicity assessment of antisense oligonucleotides

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