Augmenter of Liver Regeneration Gene Therapy Using a Novel Minicircle DNA Vector Alleviates Liver Fibrosis in Rats.

Abstract

Liver fibrosis results in cirrhosis, liver cancer, and liver failure, which is a major cause of mortality worldwide. Gene therapy is a relatively new paradigm in medicine, with enormous therapeutic potential. The development of an efficient and safe delivery system is essential for clinical gene therapy. In the present study, we evaluated augmenter of liver regeneration/growth factor ERV1-like (ALR/GFER) gene therapeutic effect mediated by a novel minicircle vector (MC-hALR). The results in liver fibrotic rats that received MC-hALR through hydrodynamics-based transfection (HBT) for 8 weeks indicated that the minicircle DNA vector produced a more effective gene therapy effect than traditional plasmids (pcDNA3.1-hALR). Even when we reduced the treatment dose of MC-hALR to 30% (w/w) and the treatment frequency from weekly to biweekly, the in vitro and in vivo results still demonstrated that higher ALR gene expression significantly blocked increases in transforming growth factor-β1 (TGF-β1), platelet derived growth factor-BB (PDGF-BB), and α-smooth muscle aorta (α-SMA) levels; effectively suppressed the production of collagens, especially collagen I; and effectively alleviated liver injury and fibrosis in rats, thereby improving the survival rate of liver fibrotic rats. It is preliminarily concluded that the relative overexpression of MC-hALR inhibits the activation of hepatic stellate cells (HSCs), thereby alleviating liver fibrosis in rats.

• Authors: Xin Wu, Guangze Liu, Mao Mu, Yuting Peng, Xiumei Li, Lisi Deng, Zhenwei Zhang, Meijuan Chen, Song You, Xiangping Kong
• Journal: Human gene therapy (Hum Gene Ther) Vol. 27 Issue 11 Pg. 880-891 (11 2016) ISSN: 1557-7422 [Electronic] United States
• PMID: 27136973 (Publication Type: Journal Article)

Chemical References

• DNA, Circular
• DNA-Binding Proteins
• KMT2D protein, human
• Neoplasm Proteins

Topics

• Animals
• DNA, Circular (genetics)
• DNA-Binding Proteins (genetics)
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Hepatic Stellate Cells (cytology)
• Liver Cirrhosis (genetics, therapy)
• Liver Regeneration
• Male
• Neoplasm Proteins (genetics)
• Rats
• Rats, Sprague-Dawley