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Related Experiment Videos

Ribozymes as tools for therapeutic target validation in arthritis.

T C Jarvis1, K S Bouhana, M E Lesch

  • 1Ribozyme Pharmaceuticals, Boulder, CO 80301, USA. tjarvis@impactbiosciences.com

Journal of Immunology (Baltimore, Md. : 1950)
|June 22, 2000
PubMed
Summary

This study validates therapeutic gene targets for arthritis using ribozymes to inhibit stromelysin mRNA. While effective in cell culture and cartilage explants, stromelysin inhibition did not prevent cartilage degradation, suggesting it

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Area of Science:

  • Molecular Biology
  • Gene Therapy
  • Rheumatology

Background:

  • Arthritic diseases involve cartilage degradation, with matrix metalloproteinases like stromelysin implicated.
  • Ribozymes offer sequence-specific RNA cleavage for potential therapeutic gene silencing.
  • Validating therapeutic gene targets is crucial for developing effective arthritis treatments.

Purpose of the Study:

  • To develop and validate a method for assessing therapeutic gene targets in arthritic disease using ribozymes.
  • To investigate the role of stromelysin in Interleukin-1 (IL-1)-induced cartilage catabolism.
  • To evaluate the efficacy of ribozymes targeting stromelysin mRNA in vitro and in vivo.

Main Methods:

  • Designed ribozymes to cleave stromelysin mRNA.

Related Experiment Videos

  • Screened ribozymes in cultured fibroblasts to identify accessible mRNA sites.
  • Developed an assay for cartilage catabolism in rabbit articular cartilage explants.
  • Administered ribozymes to explants to assess inhibition of stromelysin expression and proteoglycan degradation.

    • Main Results:

    • Identified accessible sites for ribozyme binding across the stromelysin mRNA.
    • Demonstrated sequence-specific, dose-dependent inhibition of stromelysin expression by ribozymes in cell culture.
    • Showed that ribozyme efficacy in cell culture predicted in vivo bioactivity.
    • Ribozymes inhibited IL-1-stimulated stromelysin mRNA expression in cartilage explants.
    • Stromelysin mRNA inhibition did not prevent IL-1-induced proteoglycan degradation in cartilage explants.

    Conclusions:

    • Ribozyme-mediated inhibition of stromelysin mRNA is feasible and predictive of in vivo activity.
    • Up-regulation of stromelysin is not essential for IL-1-induced cartilage catabolism.
    • This approach provides a framework for validating therapeutic gene targets in arthritic diseases.