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Recombinant adeno-associated virus vector carrying the thrombomodulin lectin-like domain for the treatment of abdominal aortic aneurysm

  • Chao-Han Lai
    Affiliations
    Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Kuan-Chieh Wang
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Tourism Management, College of Recreation and Health Management, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
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  • Cheng-Hsiang Kuo
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Fang-Tzu Lee
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Tsung-Lin Cheng
    Affiliations
    Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Bi-Ing Chang
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Yu-Jen Yang
    Affiliations
    Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Guey-Yueh Shi
    Correspondence
    Corresponding author. Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan, No. 1, University Road, Tainan 701, Taiwan.
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Hua-Lin Wu
    Correspondence
    Corresponding author. Department of Biochemistry and Molecular Biology, National Cheng Kung University College of Medicine, Tainan, Taiwan, No. 1, University Road, Tainan 701, Taiwan.
    Affiliations
    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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      Highlights

      • Optimization of thrombomodulin (TM) domains as a potential drug therapy for AAA.
      • Validation of the TM lectin-like domain (TMD1) in suppression of AAA models.
      • Developing gene therapy carrying TMD1 that exerts sustained anti-aneurysm effects.

      Abstract

      Background and aims

      Thrombomodulin (TM), through its lectin-like domain (TMD1), sequesters proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end product (RAGE) that sustains inflammation and tissue damage. Our previous study demonstrated that short-term treatment with recombinant TM containing all the extracellular domains (i.e., rTMD123) inhibits HMGB1-RAGE signaling and confers protection against CaCl2-induced AAA formation. In this study, we attempted to further optimize TM domains, as a potential therapeutic agent for AAA, using the recombinant adeno-associated virus (AAV) vector.

      Methods

      The therapeutic effects of recombinant TMD1 (rTMD1) and recombinant AAV vectors carrying the lectin-like domain of TM (rAAV-TMD1) were evaluated in the CaCl2-induced AAA model and angiotensin II-infused AAA model, respectively.

      Results

      In the CaCl2-induced model, treatment with rTMD1 suppressed the tissue levels of HMGB1 and RAGE, macrophage accumulation, elastin destruction and AAA formation, and the effects were comparable to a mole-equivalent dosage of rTMD123. In the angiotensin II-infused model, a single intravenous injection of rAAV-TMD1 (1011 genome copies), which resulted in a persistently high serum level of TMD1 for at least 12 weeks, effectively attenuated AAA formation with suppression of HMGB1 and RAGE levels and inhibition of proinflammatory cytokine production, macrophage accumulation, matrix metalloproteinase activities and oxidative stress in the aortic wall.

      Conclusions

      These findings corroborate the therapeutic potential of the TM lectin-like domain in AAA. The attenuation of angiotensin II-infused AAA by one-time delivery of rAAV-TMD1 provides a proof-of-concept validation of its application as potential gene therapy for aneurysm development.

      Keywords

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