Pyrrole-Imidazole Polyamide Targeting Transforming Growth Factor β1 Ameliorates Encapsulating Peritoneal Sclerosis

Abstract

♦ Objective: Encapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor β1 (TGF-β1) is a pivotal factor in the induction of EPS. ♦ Methods: To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-β1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-β1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and highresolution regional elasticity mapping in rats in vivo. ♦ Results: Polyamide significantly lowered mRNA expression of TGF-β1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-β1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX. ♦ Conclusions: Polyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-β1 promoter will be a specific and feasible therapeutic strategy for patients with EPS.

Contribution of TGF-β1 and Effects of Gene Silencer Pyrrole-Imidazole Polyamides Targeting TGF-β1 in Diabetic Nephropathy

“…We showed significant inhibition in human cells of TGF-β1 promoter activity and the expression of TGF-β1 mRNA and protein by PI polyamides, targeting the human TGF-β1 promoter [10]. We further showed that a PI polyamide targeting TGF-β1 could effectively retard the progression of renal diseases [11,12], post-angioplasty carotid artery stenosis [13], cornea fibrosis by alkali burns [14], skin hypertrophic scars [15], liver fibrosis [16], and encapsulating peritoneal sclerosis [17] in rats.…”

Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

“…Nevertheless, the binding of PI polyamide was reported to alter the conformation of double-stranded DNA promoter construction and impair target promoter activity [ 19 ]. We also reported that PI polyamides targeting the TGF-β1 promoter improved TGF-β1-induced fibrotic diseases such as progressive renal diseases [ 20 ], diabetic nephropathy [ 21 ], hypertrophic scar in marmoset [ 15 ], restenosis of arteries after injury [ 22 ], encapsulating peritoneal sclerosis [ 23 ], and suppressed dimethylnitrosamine-induced liver fibrosis [ 24 ]. In addition, pyridine derivative that inhibits TGF-β production improve HCV-related fibrosis and inflammation [ 25 ].…”

“…First, we did not confirm inhibition of cancer progression via TGF-β1 suppression by GB1101 in protein level. However, we previously reported the GB1101 effects on various types of diseases such as nephropathy [ 20 ], hypertrophic scar [ 15 ], restenosis of arteries after injury [ 22 ], peritoneal sclerosis [ 23 ], and liver fibrosis [ 24 ] using rat or marmoset models. Therefore, the perspective of this study is to evaluate whether GB1101 would actually be available to cancer therapy by in vivo study.…”

Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model

“…This is an advantage of PI polyamides because as gene-silencers, side effects are reduced in comparison to nucleic acid medicines such as siRNA and antisense oligonucleotides, which knock down the target gene. We have demonstrated that PI polyamides targeting TGF-β1 promoter effectively ameliorate TGF-β1-induced diseases such as progressive renal diseases [ 9 ], restenosis of arteries after injury [ 10 ], and encapsulating peritoneal sclerosis [ 15 ]. However, the PI polyamides have not yet been developed into practical medicines for clinical use.…”