Preclinical Evaluation of the Renal Toxicity of Oligonucleotide Therapeutics in Mice
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Updated: Oct 2, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Lucía Echevarría1,2, Aurelie Goyenvalle3
1Université Paris-Saclay, UVSQ, Inserm, END-ICAP, Versailles, France.
Abstract:
Antisense oligonucleotides (ASO) therapeutics hold great promise for the treatment of numerous diseases, and several ASO drugs have now reached market approval, confirming the potential of this approach. However, some candidates have also failed, due to limited biodistribution/uptake and poor safety profile. In pursuit of better delivery and higher cellular uptake, ASO are being optimized, and new chemistries are developed or conjugated with various ligands. While these developments may lead to candidates with higher potency, it is important to keep the safety aspects in sight and screen for potential toxicity in early phases of preclinical development to avoid subsequent failure in clinical development. Our understanding of ASO-mediated toxicity keeps improving with increased preclinical and clinical data available. In this chapter, we will focus on the assessment of renal toxicity in mice and describe methods to measure the levels of general urinary biomarkers as well as acute kidney injury biomarkers following ASO treatment.
Insights
Antisense oligonucleotides (ASO) show therapeutic promise but can fail due to toxicity. This chapter details methods for assessing ASO-induced renal toxicity in mice using urinary biomarkers.
Area of Science:
- Pharmacology
- Toxicology
- Drug Development
Background:
- Antisense oligonucleotides (ASO) therapeutics offer significant potential for treating various diseases, with several approved drugs.
- However, challenges such as limited biodistribution, poor cellular uptake, and safety concerns have led to clinical trial failures.
- Optimizing ASO delivery, chemistry, and ligand conjugation is crucial for enhancing potency and safety.
Purpose of the Study:
- To focus on the assessment of renal toxicity associated with ASO treatment.
- To describe methodologies for evaluating ASO-induced kidney damage in preclinical models.
- To highlight the importance of early toxicity screening in ASO drug development.
Main Methods:
- Utilizing mouse models to evaluate ASO-mediated renal toxicity.
- Measuring general urinary biomarkers to assess kidney function.
- Quantifying specific acute kidney injury (AKI) biomarkers post-ASO administration.
Main Results:
- Established methods for detecting and quantifying renal toxicity markers in response to ASO treatment.
- Provided a framework for early-stage screening of ASO candidates for nephrotoxicity.
- Contributed to a growing understanding of ASO-specific toxicity profiles.
Conclusions:
- Early assessment of renal toxicity is essential for successful ASO therapeutic development.
- Urinary biomarker analysis provides a valuable tool for monitoring ASO-induced kidney effects in mice.
- Continued research into ASO safety profiles will improve the clinical translation of these promising therapeutics.
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