Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Abstract

Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

“…In these projects, cell-and gene-based strategies, particularly gene and antisense therapies as well as RNA interference and recombinant technologies, are used (Huxley-Jones et al, 2008). Although these approaches offer fascinating new ways to treat various human diseases (Isner et al, 1996;Ye at al., 2007), they have not yet been put into clinical practice. The multiplicity and functional complexity of the ECM molecules and the diversity of diseases related to the ECM offer significant challenges for future targeting strategies.…”

“…A series of triplex-forming oligonucleotides (TFOs) have been developed for inhibiting the transcription of ␣1(I) collagen gene (Ye et al, 2005). Furthermore, bioconjugation of oligonucleotides with other molecules such as lipids, sugars, or peptides makes the site-specific delivery of TFOs possible (Ye et al, 2007). This kind of targeted delivery of TFOs provides a whole new area for antifibrotic drugs in pharmacotherapy.…”

Effect of Biejiajian Oral Liquid on the Expression of RAAS in Hepatic Fibrosis Rats

“…Under normal condition, HSC could promote the split and hyperplasia of hepatic cells and synthesize extracellular matrix [17][18][19]. HSC could also express CYPII β2, which was the key enzyme for synthesizing aldosterone and increases gradually in the formation of hepatic fibrosis [20].…”

Development and Evaluation of Nano‑scale Systems for Targeted Delivery to Treat Liver Fibrosis

“…197 The entire region spanning from -140 to -200 of α1(I) collagen gene promoter exist as a symmetric polypurine-polypyrimidine tract in which the polypyrimidine sequence at -141 to -170 is called C1 region present on the non-coding strand, whereas the adjacent polypurine sequence from -171 to -200 is called C2 region located on the coding strand. The cis-acting element is the C1 and C2 regions, playing an important role in collagen transcription.…”

“…197 Activation of HSCs affects liver architecture and eventually liver function. 198 Until now, no pharmaceutical intervention is available to treat this fibrotic disease.…”