Short-term efficiency and safety of gene delivery into canine kidneys.
BACKGROUND
Gene delivery of biologically active molecules to the kidney may have potential therapeutic applications in renal and cardiovascular diseases. Recombinant adenovirus is one of the most efficient vectors for in vivo gene delivery. However, in vivo toxicity at the site of administration has to be evaluated for the successful use of adenovirus-mediated gene transfer. The aim of this study was to document precisely the short-term safety of 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 routes, i.e. intra-renal-ureteral route (IU) and intra-renal-arterial route with (IAC) or without (IA) clamping of the renal vein. Toxicity of viral administration was assayed on day 4 at both physiological and histological levels. Renal samples were monitored for the presence of nuclear beta-galactosidase-expressing cells.


RESULTS
All renal physiological parameters (glomerular filtration rate, effective renal plasma flow, and electrolyte excretion fractions) remained stable whatever the route of viral administration. No histological lesion was detected in any of the haematoxylin-eosin-stained kidney sections, and there was no evidence of ischaemia-reperfusion injury in the kidneys subjected to venous clamping. Efficient transgene expression was obtained in dog kidneys following IAC and IU injection of adenoviral vectors. Gene transfer via the IAC route induced gene expression predominantly in the cortical interstitial cells. Retrograde IU adenoviral injection resulted in reduced transduction efficiency compared with the IAC route, with transgene expression occurring mainly in the distal tubular and pyelic epithelial cells.


CONCLUSIONS
The two major findings of this study were (i) the absence of acute histological and functional renal alteration following intra-arterial and intra-ureteral injections of adenoviral vectors in both kidneys of healthy dogs, and (ii) the efficiency of transgene expression with specific cellular targeting according to the route of administration.
Unité de Cardiologie d'Alfort, CHU Henri-Mondor, Créteil, France.
V
V
Chetboul
B
B
Klonjkowski
H P
HP
Lefebvre
D
D
Desvaux
V
V
Laroute
D
D
Rosenberg
C
C
Maurey
F
F
Crespeau
M
M
Adam
S
S
Adnot
M
M
Eloit
J L
JL
Pouchelon
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004285:Dogs; D004526:Efficiency; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000592:standards*; D005822:Genetic Vectors; D007267:Injections; D007668:Kidney; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D012077:Renal Artery; D012449:Safety; D013997:Time Factors; D014161:Transduction, Genetic; D014513:Ureter; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D001616:beta-Galactosidase