Targeted inhibition of type I procollagen synthesis by antisense DNA oligonucleotides

Abstract

In hepatic fibrosis, the connective tissue biomatrix of the liver changes from the normal matrix, rich in basement membrane collagens, to a matrix enriched in interstitial fibrillar collagens. Type I collagen is the predominant component of thick fibrous bands found in matrix in advanced fibrosis. The aim of the current research was to determine whether a therapeutic approach could be developed that would specifically target collagen-producing cells to reduce the synthesis and accumulation of type I collagen. Antisense DNA oligonucleotides directed against specific sequences within α1(I) and α2(I) mRNA of type I procollagen were complexed to a cell-specific carrier, and screened for their effectiveness in reducing α1(I) and α2(I) mRNA levels. Two antisense DNA oligonucleotides delivered by the carrier were found to be most effective in reducing α1(I) and α2(I) mRNA and total collagen accumulation in the cells, but had no effect on reducing β-actin mRNA in the same cells. At similar concentrations, free antisense DNA oligonucleotides were not effective in inhibiting collagen synthesis, and/or in decreasing cellular concentrations of α1(I) or α2(I) mRNA. Collagen synthesis and mRNA levels in cells lacking receptors that recognize the carrier protein were not changed after treatment with complexed antisense DNA. The results indicate that antisense oligonucleotides can be targeted to cell types, and were effective inhibiting collagen synthesis in those cells.