Abstract
We report a preclinical study of a pyrrole-imidazole (PI) polyamide that targets the human transforming growth factor (hTGF)-β1 gene as a novel transcriptional gene silencer in a common marmoset primate model. We designed and then synthesized PI polyamides to target the hTGF-β1 promoter. We examined effects of seven PI polyamides (GB1101-1107) on the expression of hTGF-β1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in human vascular smooth muscle cells. GB1101, GB1105 and GB1106 significantly inhibited hTGF-β1 mRNA expression. We examined GB1101 as a PI polyamide to hTGF-β1 for hypertrophic scars in marmosets in vivo. Injection of GB1101 completely inhibited hypertrophic scar formation at 35 days post-incision and inhibited cellular infiltration, TGF-β1 and vimentin staining, and epidermal thickness. Mismatch polyamide did not affect hypertrophic scarring or histological changes. Epidermis was significantly thinner with GB1101 than with water and mismatch PI polyamides. We developed the PI polyamides for practical ointment medicines for the treatment of hypertrophic scars. FITC-labeled GB1101 with solbase most efficiently distributed in the nuclei of epidermal keratinocytes, completely suppressed hypertropic scarring at 42 days after incision, and considerably inhibited epidermal thickness and vimentin-positive fibroblasts. PI polyamides targeting hTGF-β1 promoter with solbase ointment will be practical medicines for treating hypertrophic scars after surgical operations and skin burns.
Highlights
Novel translational medicines such as molecularly-targeted drugs and monoclonal antibodies have been introduced into clinical practice [1]
To determine the lead compounds, we examined the effects of seven PI polyamides (GB11011107) targeting human transforming growth factor (hTGF)-β1 promoter on human transforming growth factor (TGF)-β1 (hTGF-β1) mRNA expression in human vascular smooth muscle cells (VSMCs)
GB1101 and GB1105 significantly inhibited expression of hTGF-β1 mRNA stimulated with phorbol 12-myristate 13-acetate (PMA) in a dose-dependent manner (p < 0.05), whereas GB1106 significantly inhibited expression of hTGF-β1 mRNA from 10-8 to 10-5 M PI polyamides to the same level as baseline expression (p < 0.01)
Summary
Novel translational medicines such as molecularly-targeted drugs and monoclonal antibodies have been introduced into clinical practice [1]. Nucleic acid medicines like antisense deoxynucleotides and ribozymes and decoys were developed as next-generation therapeutic medicines These agents can be degraded by nucleases like DNase or RNase, and efficient systems of drug delivery are required for adequate distribution in organs. The small synthetic molecules of PI polyamides consist of aromatic rings of amino acids N-methylpyrrole and N-methylimidazole that recognize and bind to DNA with sequence specificity [2,3]. The applicability of PI polyamides as novel gene therapy agents might be greater than that of nucleic acid medicines [6]. Various sequence-specific DNA-binding PI polyamides have been created to control gene expression. PI polyamides targeting TGF-β1 may be a feasible gene silencer for treating hypertrophic scars and keloids
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