Circulation, Vol 89, 2161-2169, Copyright © 1994 by American Heart Association
MS Conte, LK Birinyi, T Miyata, JT Fallon, HK Gold, AD Whittemore and RC Mulligan
BACKGROUND: In an effort to determine whether specific genetic
modifications of cells of the vascular system might improve the efficacy of
existing clinical procedures such as endarterectomy, atherectomy, and
percutaneous angioplasty, we investigated the utility of gene transfer to
rapidly and efficiently repopulate injured arteries with genetically
modified cells in an animal model. METHODS AND RESULTS: The method involves
the harvest of autologous venous-derived endothelial cells, the efficient
genetic modification of the cells through the use of recombinant
retroviruses, and the subsequent implantation of the genetically modified
cells on the surface of balloon-denuded arterial segments. With a rabbit
model, freshly isolated endothelial cells were transduced with a
recombinant retrovirus encoding the bacterial enzyme beta-galactosidase.
The autologous transduced cells were then implanted on the surface of
balloon-denuded ileofemoral arterial segments at different cell densities;
after 1 to 14 days, the animals were killed, and the vessel segments were
examined. Cells expressing the bacterial gene product, as determined by in
situ staining for beta-galactosidase, were found to be present on the
surface of 28 of the 32 arteries seeded with genetically modified cells.
Vessels examined at 4 to 7 days after seeding displayed 40% to 90% coverage
with transduced cells, even when seeded at subconfluent density, and an
intact endothelial cell monolayer, as evidenced by scanning electron
microscopy studies. Vessels examined at 14 days after seeding revealed more
variable staining for beta- galactosidase yet, again, in most cases, an
intact endothelial cell monolayer. CONCLUSIONS: These studies indicate the
feasibility of generating segments of arterial vessels containing
genetically modified cells in a rapid and efficient fashion. Further
studies are now necessary to determine whether the local expression of
specific polypeptides within a region of vessel for a finite period of time
will be clinically useful.
ARTICLES
Efficient repopulation of denuded rabbit arteries with autologous genetically modified endothelial cells
Whitehead Institute for Biomedical Research, Cambridge Center, MA 02142.
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