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  • Acquired Diseases
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Blockade of TGF-β by in vivo gene transfer of a soluble TGF-β type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis

Gene Therapy volume 7, pages 1915–1924 (2000)Cite this article

Abstract

Accumulating evidence suggests the involvement of TGF-β in the process of corneal opacity, which is one of the serious causes of visual loss. However, whether TGF-β is indeed critical for the pathogenesis remains unknown. We constructed an adenovirus expressing an entire ectodomain of the human type II TGF-β receptor fused to Fc portion of human IgG (AdTβ-ExR): this soluble receptor is secreted from AdTβ-ExR-infected cells, binds to TGF-β and inhibits TGF-β signaling. When AdTβ-ExR was injected into the femoral muscle of Balb/c mice, a high level of the soluble receptor protein (2.0–3.5 × 103 pM) was detectable in the serum and in the ocular fluid for at least 10 days. In the mice subjected to corneal injury with silver nitrate and to intramuscular injection with either saline or a control adenovirus expressing β-galactosidase (AdLacZ), corneal opacification composed of extracellular matrix (ECM) accumulation, of infiltration of neutrophils and monocytes/macrophages, and of angiogenesis were all induced. In contrast, they were markedly reduced in the mice injected with AdTβ-ExR. Immunohistochemical analysis revealed that TGF-β, fibronectin, macrophage chemoattractant protein-1, and vascular endothelial growth factor were densely stained in the edge of wounded cornea, but they were scarcely present in the injured-cornea of AdTβ-ExR-treated mice. Our results demonstrate that TGF-β indeed plays a critical role in the process of cornea opacification, and that adenovirus-mediated expression of a soluble TGF-β receptor can be therapeutically useful.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from Ministry of Education, Science and Culture of the Japanese Government (to TS and HU), and by the grants from Japan National Society for the Prevention of Blindness (Tokyo, Japan), from the Fukuoka Anti-Cancer Association (Fukuoka, Japan), from Kaibara Morikazu Medical Science Promotion Foundation (Fukuoka, Japan), from The Casio Science Promotion Foundation (Tokyo, Japan) (to TS), and from Takeda Medical Research Foundation and from Tokyo Biochemical Society (HU). We also thanks Drs H Yamashita and K Miyazono for their kind gift of TGF-β antibodies and Drs H Sanui and M Uehara for their financial support.

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Authors and Affiliations

  1. Department of Ophthalmology, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    T Sakamoto, K Sonoda, T Hisatomi & H Inomata

  2. Department of Molecular Cardiology, Kyushu University Graduate School of Medicine, Fukuoka, Japan

    H Ueno

  3. Pharmaceutical Research Laboratory, Kirin Brewery, Takasaki, Japan

    K Shimizu & H Ohashi

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  1. T Sakamoto
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Sakamoto, T., Ueno, H., Sonoda, K. et al. Blockade of TGF-β by in vivo gene transfer of a soluble TGF-β type II receptor in the muscle inhibits corneal opacification, edema and angiogenesis. Gene Ther 7, 1915–1924 (2000). https://doi.org/10.1038/sj.gt.3301320

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