Enhanced transduction of fibroblasts in transplanted kidney with an adenovirus having an RGD motif in the HI loop.
Application of gene therapy to the renal graft has a powerful potential to improve the outcome of kidney transplantation and eliminate detrimental side effects associated with systemic therapy, through local expression of immunoregulatory or other protective molecules. However, the search for the optimal vector is still ongoing. In this study, we used a modified adenovirus that has an Arg-Gly-Asp (RGD) motif inserted in the HI loop of the fiber knob, as a successful strategy to transduce the renal graft. Donor Lewis rat kidneys were infused via the renal artery with a solution containing either a fiber-modified adenovirus (AdTL-RGD) or an unmodified adenovirus (AdTL), or with saline. Syngeneic recipients were killed after 3, 7 or 14 days. Efficiency, selectivity, localization, time course of gene expression and side effects were studied using biochemical and immunohistological techniques. Enhanced gene expression was achieved selectively in the transplanted kidney by AdTL-RGD, when compared to AdTL. Transgene expression lasted for at least 2 weeks. With the AdTL-RGD vector, the transgene was abundantly expressed in the renal interstitial fibroblasts. An increase in the number of cytotoxic T lymphocytes accompanied the use of either vector, when compared to saline. These data convincingly show enhanced and selective gene transfer to the fibroblasts of transplanted kidneys using an RGD-modified adenovirus, providing a highly efficient vector system for future therapeutic interventions.
Sandovici
M
M
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, Faculty of Medical Sciences, University Medical Center Groningen, Groningen, The Netherlands. m.sandovici@med.umcg.nl
Deelman
L E
LE
Smit-van Oosten
A
A
van Goor
H
H
Rots
M G
MG
de Zeeuw
D
D
Henning
R H
RH
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D007165:Immunosuppression Therapy; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D009842:Oligopeptides; D051381:Rats; D011917:Rats, Inbred Lew; D019076:Transgenes
D036022:Capsid Proteins; D009842:Oligopeptides; C018315:hexon capsid protein, Adenovirus; C047981:arginyl-glycyl-aspartic acid