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Comparison of the Class Effects of Antisense Oligonucleotides in CByB6F1-Tg(HRAS)2Jic and CD-1 Mice

Tae-Won Kim1, Chris N Papagiannis2, Laura S Zwick2

  • 11 Ionis Pharmaceutical, Carlsbad, California, USA.

Toxicologic Pathology
|December 27, 2018
PubMed

Insights

The Tg.rasH2 mouse model is a viable alternative for carcinogenicity studies of antisense oligonucleotides (ASOs). Data from CD-1 mice can inform dose selection for Tg.rasH2 studies due to similar biological responses across mouse strains.

Area of Science:

  • Pharmacology and Toxicology
  • Genetics and Genomics
  • Preclinical Research

Background:

  • The Tg.rasH2 mouse model offers a shorter alternative to traditional 2-year carcinogenicity studies.
  • Key questions remain regarding strain-specific biological responses to antisense oligonucleotides (ASOs) in this model.
  • Understanding these differences is crucial for effective dose selection and study design.

Purpose of the Study:

  • To evaluate potential differences in biological responses to 2'- O-(2-methoxyethyl) antisense oligonucleotides (ASOs) across different mouse strains.
  • To determine if data from CD-1 mice can be reliably used for dose setting in Tg.rasH2 carcinogenicity studies.
  • To assess the utility of the Tg.rasH2 model as an alternative to the CD-1 mouse carcinogenicity study for ASOs.

Main Methods:

  • Administration of four distinct 2'- O-(2-methoxyethyl) ASOs to CByB6F1 (wild type), Tg.rasH2 (hemizygous), and CD-1 mice.
  • Comprehensive evaluation including clinical signs, body weight, food consumption, serum chemistry, hematology, and histopathology.
  • Analysis of cytokine/chemokine profiles and liver ASO concentrations to compare strain-specific responses.

Main Results:

  • No significant differences were observed in clinical signs, body weight, food consumption, or hematology/serum chemistry across the tested mouse strains.
  • Histopathology revealed minimal differences in the type or severity of observed changes among CD-1, CByB6F1, and Tg.rasH2 mice.
  • Cytokine/chemokine responses and liver ASO concentrations were comparable between strains, indicating similar systemic exposure and biological effects.

Conclusions:

  • The biological responses to the tested ASOs were not meaningfully different between CD-1, CByB6F1, and Tg.rasH2 mice.
  • Nonclinical data generated in CD-1 mice can be effectively utilized for dose selection and predicting effects in the Tg.rasH2 mouse model.
  • This supports the Tg.rasH2 model's use as an acceptable alternative for ASO carcinogenicity testing, streamlining drug development.
Keywords:
ASOCByB6F1-Tg(HRAS)2JicantisensecarcinogenicityoligonucleotiderasH2

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