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

T. Sakamoto, H. Ueno, K. Sonoda, T. Hisatomi, K. Shimizu, H. Ohashi, H. Inomata

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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 x 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.

Original languageEnglish
Pages (from-to)1915-1924
Number of pages10
JournalGene Therapy
Volume7
Issue number22
DOIs
Publication statusPublished - Jan 1 2000

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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