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