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Urinary Kidney Biomarker Panel Detects Preclinical Antisense Oligonucleotide-Induced Tubular Toxicity

Åsa Sandelius1, Jayati Basak1, Mikko Hölttä1

  • 1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, 128698AstraZeneca R&D, Gothenburg, Sweden.

Toxicologic Pathology
|October 21, 2020
PubMed

Insights

This study shows that a panel of urine biomarkers can detect kidney damage caused by antisense oligonucleotide (ASO) drugs in preclinical mouse models. These biomarkers, including kidney injury molecule 1 (KIM-1), are sensitive indicators of ASO-induced kidney toxicity.

Area of Science:

  • Pharmacology
  • Toxicology
  • Biomarker Discovery

Background:

  • Sensitive kidney safety assessment is crucial for drug development.
  • The FDA qualified a panel of 6 urine biomarkers for kidney toxicity monitoring in early clinical trials.
  • This panel's utility in preclinical models and for novel drug modalities like antisense oligonucleotides (ASOs) requires further evaluation.

Purpose of the Study:

  • To assess the utility of a qualified urine biomarker panel in detecting kidney toxicity induced by a constrained ethyl ASO in mice.
  • To compare the biomarker responses to a toxic ASO versus a control ASO with similar chemistry.

Main Methods:

  • Mice were dosed with a toxic ASO and a control ASO at varying concentrations.
  • Kidney histopathology was evaluated.
  • Urine concentrations of 6 biomarkers (clusterin, cystatin C, KIM-1, N-acetyl-β-d-glucosaminidase, NGAL, osteopontin) were measured and normalized to creatinine.
  • Biomarker levels were correlated with observed kidney pathology.

Main Results:

  • The toxic ASO induced mild proximal tubular pathology and elevated KIM-1, clusterin, NGAL, and cystatin C levels.
  • A dose-dependent relationship was observed between ASO exposure, histopathology, and biomarker elevations.
  • The control ASO unexpectedly caused mild elevations in KIM-1, NGAL, and cystatin C without apparent kidney damage.
  • KIM-1 and clusterin showed the strongest correlation with kidney pathology severity.

Conclusions:

  • The qualified biomarker panel is a sensitive tool for detecting preclinical kidney toxicity induced by ASOs.
  • KIM-1 and clusterin are particularly promising biomarkers for ASO-induced kidney injury.
  • Further research is needed to understand the mechanism behind control ASO-induced biomarker elevations.
Keywords:
KIM-1N-acetyl-β-d-glucosaminidaseNGALantisense oligonucleotideclusterincystatin Costeopontin

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