Preclinical Study of Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Human TGF-β1 Promoter for Hypertrophic Scars in a Common Marmoset Primate Model.
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.
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.
Jun
J
Igarashi
Division of Life Science, Advanced Research Institute for the Sciences and Humanities, Nihon University Graduate School, Tokyo, Japan; Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Noboru
N
Fukuda
Marmoset Research Department, Central Institute for Experimental Animals, Kanagawa, Japan.
Takashi
T
Inoue
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.
Shigeki
S
Nakai
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.
Kosuke
K
Saito
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.
Kyoko
K
Fujiwara
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan.
Hiroyuki
H
Matsuda
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Takahiro
T
Ueno
Department of Clinical Pharmacokinetics, College of Pharmacy, Nihon University, Chiba, Japan.
Yoshiaki
Y
Matsumoto
Department of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan.
Takayoshi
T
Watanabe
Department of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan.
Hiroki
H
Nagase
Department of Chemistry, Kyoto University Graduate School, Kyoto, Japan.
Toshikazu
T
Bando
Department of Chemistry, Kyoto University Graduate School, Kyoto, Japan.
Hiroshi
H
Sugiyama
Marmoset Research Department, Central Institute for Experimental Animals, Kanagawa, Japan.
Toshio
T
Itoh
Department of General Medicine, Nihon University School of Medicine, Tokyo, Japan; Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Masayoshi
M
Soma
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002144:Callithrix; D017439:Cicatrix, Hypertrophic / Q000628:therapy*; D004195:Disease Models, Animal; D020868:Gene Silencing; D018390:Gene Targeting; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007267:Injections; D008297:Male; D008969:Molecular Sequence Data; D009757:Nylons / Q000737:chemistry*; D009824:Ointments; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D007093:Imidazoles; D009757:Nylons; D009824:Ointments; D011758:Pyrroles; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C029899:imidazole