Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF
Connective tissue growth factor (CTGF) is notably upregulated in scar tissue, making it a promising target for therapeutic intervention. Here, we have designed and screened an antisense oligonucleotide (ASO) that binds specifically to the exon five sequence of CTGF, with particular emphasis on the u...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1623640/full |
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| author | Jinhe Li Xi Wu Ying Yang Ruiqi Mao Zherui Li Xiujun Zhang Wenguo Wei Wendi Wang Hailong Li Honggang Zhou Cheng Yang Cheng Yang |
| author_facet | Jinhe Li Xi Wu Ying Yang Ruiqi Mao Zherui Li Xiujun Zhang Wenguo Wei Wendi Wang Hailong Li Honggang Zhou Cheng Yang Cheng Yang |
| author_sort | Jinhe Li |
| collection | DOAJ |
| description | Connective tissue growth factor (CTGF) is notably upregulated in scar tissue, making it a promising target for therapeutic intervention. Here, we have designed and screened an antisense oligonucleotide (ASO) that binds specifically to the exon five sequence of CTGF, with particular emphasis on the use of 2′-O-methoxyethyl (MOE) and locked nucleic acid (LNA) modifications to enhance stability and specificity. In vitro experiments demonstrated that both MOE-ASO#1 and LNA-ASO#1 significantly inhibited fibroblast proliferation and extracellular matrix protein expression. In vivo studies using mouse and rabbit scar models, as well as a nude mouse keloid xenograft model, revealed that these ASOs effectively reduced scar formation and keloid growth while also suppressing IL-6 expression. LNA-ASO#1 showed superior pharmacodynamics compared to MOE-ASO#1. Mechanistic investigations indicated that the ASOs exert their antifibrotic effects by inhibiting the TGF-β1 pathway, myofibroblast activation, and extracellular matrix production. These findings suggest that LNA-ASO#1 is a promising therapeutic strategy for the treatment of scars. |
| format | Article |
| id | doaj-art-83f1dedd907c4cbe95d237c07b98ea86 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-83f1dedd907c4cbe95d237c07b98ea862025-08-21T05:27:33ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-08-011610.3389/fphar.2025.16236401623640Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGFJinhe Li0Xi Wu1Ying Yang2Ruiqi Mao3Zherui Li4Xiujun Zhang5Wenguo Wei6Wendi Wang7Hailong Li8Honggang Zhou9Cheng Yang10Cheng Yang11State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaDepartment of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, ChinaDepartment of Dermatology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, ChinaDepartment of Plastic and Burn Surgery, Tianjin First Central Hospital, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaState Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, ChinaNankai International Advanced Research Institute (Shenzhen Futian), ShenZhen, ChinaConnective tissue growth factor (CTGF) is notably upregulated in scar tissue, making it a promising target for therapeutic intervention. Here, we have designed and screened an antisense oligonucleotide (ASO) that binds specifically to the exon five sequence of CTGF, with particular emphasis on the use of 2′-O-methoxyethyl (MOE) and locked nucleic acid (LNA) modifications to enhance stability and specificity. In vitro experiments demonstrated that both MOE-ASO#1 and LNA-ASO#1 significantly inhibited fibroblast proliferation and extracellular matrix protein expression. In vivo studies using mouse and rabbit scar models, as well as a nude mouse keloid xenograft model, revealed that these ASOs effectively reduced scar formation and keloid growth while also suppressing IL-6 expression. LNA-ASO#1 showed superior pharmacodynamics compared to MOE-ASO#1. Mechanistic investigations indicated that the ASOs exert their antifibrotic effects by inhibiting the TGF-β1 pathway, myofibroblast activation, and extracellular matrix production. These findings suggest that LNA-ASO#1 is a promising therapeutic strategy for the treatment of scars.https://www.frontiersin.org/articles/10.3389/fphar.2025.1623640/fullCTGFantisense oligonucleotidescarLNAfibrosis |
| spellingShingle | Jinhe Li Xi Wu Ying Yang Ruiqi Mao Zherui Li Xiujun Zhang Wenguo Wei Wendi Wang Hailong Li Honggang Zhou Cheng Yang Cheng Yang Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF Frontiers in Pharmacology CTGF antisense oligonucleotide scar LNA fibrosis |
| title | Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF |
| title_full | Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF |
| title_fullStr | Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF |
| title_full_unstemmed | Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF |
| title_short | Locked nucleic acid-modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of CTGF |
| title_sort | locked nucleic acid modified antisense oligonucleotides attenuate scar hyperplasia through targeted inhibition of ctgf |
| topic | CTGF antisense oligonucleotide scar LNA fibrosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1623640/full |
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