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

Atherosclerosis
Chao-Han LaiHua-Lin Wu

Abstract

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. 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. 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 lev...Continue Reading

Citations

Apr 10, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Changbin SunBo Yu
Jul 6, 2019·Annals of Vascular Diseases·Takashi MiyakeRyuichi Morishita
Oct 13, 2020·Frontiers in Immunology·Kanako Watanabe-KusunokiTatsuya Atsumi
Feb 12, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·James PhieJonathan Golledge
Mar 27, 2021·Molecular Therapy. Methods & Clinical Development·Anca RemesOliver J Müller
Feb 9, 2020·European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery·Chao-Han LaiTsung-Lin Cheng

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