Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts

Michael W. Kilpatrick, Leonidas A. Phylactou, Maurice Godfrey, Catherine H. Wu, George Y. Wu, Petros Tsipouras

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27 Scopus citations


The hammerhead ribozyme is a small catalytic RNA molecule. Potential hammerhead ribozymes that possess a catalytic domain and flanking sequence complementary to a target mRNA can cleave in trans at a putative cleavage site within the target molecule. We have investigated the potential of hammerhead ribozymes to down-regulate the product of the fibrillin-l gene (FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of the elastin-associated microfibrils. Mutations in the FBN1 gene are responsible for Marfan syndrome (MFS), a common systemic disorder of the connective tissue. Many FBN1 mutations responsible for MFS appear to act in a dominant-negative fashion, raising the possibility that reduction of the amount of product from the mutant FBN1 allele might be a valid therapeutic approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to the 5' end of the human FBN1 mRNA has been designed and synthesized, and shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is magnesium dependent and efficient at both 37 and 50°C. Delivery of the FBN1-RZI ribozyme into cultured dermal fibroblasts, by receptor-mediated endocytosis of a ribozymetransferrin-polylysine complex, specifically reduces both cellular FBN1 mRNA and the deposition of fibrillin in the extracellular matrix. These results suggest that the use of hammerhead ribozymes is a valid approach to the study of fibrillin gene expression and possibly to the development of a therapeutic approach to MFS.

Original languageEnglish (US)
Pages (from-to)1939-1944
Number of pages6
JournalHuman Molecular Genetics
Issue number12
StatePublished - Dec 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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