Circulation, Vol 90, 1648-1656, Copyright © 1994 by American Heart Association
PG Steg, LJ Feldman, JY Scoazec, O Tahlil, JJ Barry, S Boulechfar, T Ragot, JM Isner and M Perricaudet
BACKGROUND: Previous investigations in live animals convincingly
established that arterial gene transfer, while feasible, was compromised by
a low transfection efficiency. More recent studies have shown that
transfection efficiency may be substantially augmented by the use of
recombinant adenoviral vectors. Most in vivo transfections reported to
date, however, have used direct (operative) administration of the
adenoviral vector. Clinical applications of arterial gene transfer (such as
prevention of restenosis), however, would require local percutaneous
delivery of the transgene. The present study was designed to extend in vivo
intraoperative findings to percutaneous delivery system and to assess
whether gene transfer remains site specific. METHODS AND RESULTS: A
recombinant, replication-defective adenovirus modified to include an
expression cassette for nucleus- targeted beta-galactosidase was introduced
into rabbit iliac arteries in vivo using either a double-balloon catheter
(DBC, n = 27) or a hydrogel-coated balloon catheter (HBC, n = 27).
Contralateral arteries- normal, endothelium-denuded, or sham-transfected
with a control adenoviral vector-served as controls. beta-Galactosidase
expression was assessed by X-Gal staining. Cell-transduction efficiency was
measured by morphometric analysis. Polymerase chain reaction (PCR) and
histochemistry were used to detect the presence and/or expression of viral
DNA in remote organs. Transgene expression was detected in all cases (46 of
46) between 3 and 14 days after transfection but was in no case detectable
28 days after transfection. In the DBC group, transgene expression was
limited to endothelial cells when the endothelium was left intact and to
rare medial cells (< 2.2%) when it had been removed. In contrast, HBC
delivery resulted in transduction of up to 9.6% of medial smooth muscle
cells (P = .0001). Optimized PCR and histochemistry failed to detect
evidence of extra-arterial transfection except in a small number of cells
(between 1 in 3 x 10(2) and 1 in 3 x 10(5) cells) in the livers of 2
animals in the DBC group. CONCLUSIONS: (1) Efficient, adenovirus-mediated,
arterial gene transfer to endothelial and/or smooth muscle cells is
feasible by percutaneous, clinically applicable techniques. (2) Consistent
transfection of medial smooth muscle cells may be achieved when the
endothelial layer is abraded. (3) Medial transfection is more efficient
when an HBC, rather than a DBC, is used. (4) Percutaneous delivery of the
adenoviral vector via HBC results in site-specific arterial gene transfer.
Very-low-level extra-arterial transfection may occur, however, when the DBC
is used.
ARTICLES
Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an adenoviral vector
Unite Physiopathologie du Coeur et des Arteres, Faculte Bichat, Paris, France.
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