Modulation of renal glomerular disease using remote delivery of adenoviral-encoded solubletype II TGF-beta receptor fusion molecule.
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 AdTbeta-ExR and AdCATbeta-TR. AdTbeta-ExR encodes a chimeric soluble molecule comprising the entire ectodomain of the human type II TGF-beta receptor, genetically fused to the Fc fragment of the human IgG1 (sTbetaRII), while AdCATbeta-TR encodes only the dominant-negative truncated ectodomain of the human type II TGF-beta receptor. The biologic activity of the type II TGF-beta 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 sTbetaRII was evaluated immunohistochemically after intramuscular (IM) delivery of AdTbeta-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
sTbetaRII was detected in the glomeruli after remote IM injection of AdTbeta-ExR, but not the control AdCATbeta-TR, indicating renal deposition of the heterologous soluble fusion protein after its expression in the muscle and secretion into the circulation. AdTbeta-ExR, but not AdCATbeta-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-beta receptor over a dominant-negative, non-soluble type II TGF-beta receptor in the context of blocking renal fibrosis in murine models.
Haviv
Yosef S
YS
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Takayama
Koichi
K
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nagi
Peter A
PA
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Tousson
Albert
A
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
Cook
William
W
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Wang
Minghui
M
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Lam
John T
JT
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Naito
Seiji
S
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Lei
Xiaosheng
X
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Carey
Delicia E
DE
Department of Medical Statistics, University of Alabama at Birmingham, Birmingham, AL, USA.
Curiel
David T
DT
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005921:Glomerulonephritis / Q000235:genetics / Q000628:therapy; D007273:Injections, Intramuscular; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II