Modulation of renal glomerular disease using remote delivery of adenoviral-encoded soluble type II TGF-β receptor fusion molecule

Yosef S. Haviv, Koichi Takayama, Peter A. Nagi, Albert Tousson, William Cook, Minghui Wang, John T. Lam, Seiji Naito, Xiaosheng Lei, Delicia E. Carey, David T. Curiel

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background: Systemic adenoviral (Ad) gene therapy for renal disorders is largely hampered by the unique architecture of the kidney. Consequently, currently available Ad vectors are of only limited therapeutic utility in the context of glomerular and fibroproliferative renal diseases. Methods: The Ad vectors studied in the context of blocking renal fibrosis were AdTβ-ExR and AdCATβ-TR. AdTβ-ExR encodes a chimeric soluble molecule comprising the entire ectodomain of the human type II TGF-β receptor, genetically fused to the Fc fragment of the human IgG1 (sTβRII), while AdCATβ-TR encodes only the dominant-negative truncated ectodomain of the human type II TGF-β receptor. The biologic activity of the type II TGF-β receptor was evaluated in vitro by its ability to inhibit cellular proliferation and in vivo in a unilateral ureter obstruction fibrosis model. Renal targeting with sTβRII was evaluated immunohistochemically after intramuscular (IM) delivery of AdTβ-ExR. The renal antifibrotic effect of the Ad vectors was evaluated in a lupus murine model with both light and electron microscopy and urinalysis. Results: sTβRII was detected in the glomeruli after remote IM injection of AdTβ-ExR, but not the control AdCATβ-TR, indicating renal deposition of the heterologous soluble fusion protein after its expression in the muscle and secretion into the circulation. AdTβ-ExR, but not AdCATβ-TR, could transiently inhibit mesangial expansion, glomerular hypercellularity, proteinuria and cortical interstitial fibrosis in a murine lupus model. However, the autoimmune renal disease eventually surpassed the antifibrotic effect. Conclusions: These results indicate the superiority of a soluble type II TGF-β receptor over a dominant-negative, non-soluble type II TGF-β receptor in the context of blocking renal fibrosis in murine models.

Original languageEnglish
Pages (from-to)839-851
Number of pages13
JournalJournal of Gene Medicine
Volume5
Issue number10
DOIs
StatePublished - 1 Oct 2003
Externally publishedYes

Keywords

  • Adenovirus
  • Experimental glomerulonephritis
  • Gene therapy
  • Renal fibrosis
  • Transforming growth factor-β receptor type II
  • Unilateral ureter obstruction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

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