Short-term efficiency and safety of gene delivery into canine kidneys

Background. Gene delivery of biologically active molecules to the kidney ma y have potential therapeutic applications in renal and cardiovascular disea ses. Recombinant adenovirus is one of the most efficient vectors for in viv o gene delivery. However, in vivo toxicity at the site of administration ha s to be evaluated for the successful use of adenovirus-mediated gene transf er. The aim of this study was to document precisely the short-term safety o f different routes of intra-renal adenoviral administration and to compare their transduction efficiency. Methods. Dog puppies were injected with an adenoviral vector expressing the beta -galactosidase reporter gene in both kidneys via three different rout es, i.e. intra-renal-ureteral route (IU) and intra-renal-arterial route wit h (IAC) or without (IA) clamping of the renal vein. Toxicity of viral admin istration was assayed on day 4 at both physiological and histological level s. Renal samples were monitored for the presence of nuclear beta -galactosi dase-expressing cells. Results. All renal physiological parameters (glomerular filtration rate, ef fective renal plasma flow, and electrolyte excretion fractions) remained st able whatever the route of viral administration. No histological lesion was detected in any of the haematoxylin-eosin-stained kidney sections, and the re was no evidence of ischaemia-reperfusion injury in the kidneys subjected to venous clamping. Efficient transgene expression was obtained in dog kid neys following IAC and IU injection of adenoviral vectors. Gene transfer vi a the IAC route induced gene expression predominantly in the cortical inter stitial cells. Retrograde IU adenoviral injection resulted in reduced trans duction efficiency compared with the IAC route, with transgene expression o ccurring mainly in the distal tubular and pyelic epithelial cells. Conclusions. The two major findings of this study were (i) the absence of a cute histological and functional renal alteration following intra-arterial and intra-ureteral injections of adenoviral vectors in both kidneys of heal thy dogs, and (ii) the efficiency of transgene expression with specific cel lular targeting according to the route of administration.