Circulation, Vol 90, 2414-2424, Copyright © 1994 by American Heart Association
BA French, W Mazur, RS Geske and R Bolli
BACKGROUND--Efficient methods of introducing genes into myocardial cells
must be developed before local somatic cell gene therapy can be implemented
against myocardial disease. Although adenoviral (Ad5) vectors have been
used to target rodent hearts and plasmid DNA has been directly injected
into the myocardium of rats and dogs, the amounts of recombinant protein
produced by these procedures have not been reported, and adenoviral vectors
have not been used in large mammalian hearts. METHODS AND
RESULTS--Replication-deficient recombinant adenoviral vectors carrying
either the luciferase or lacZ reporter genes were injected directly into
the ventricular myocardium of adult domestic swine for evaluation of
reporter gene expression. This procedure did not affect regional myocardial
function as assessed by systolic wall thickening using ultrasonic crystals.
Luciferase activity was detected 3 days after injection, increased markedly
at 7 days, and then declined progressively at 14 and 21 days. Luciferase
production was comparable in the right and left ventricular walls and
increased with increasing amounts of virus, reaching 61 +/- 21 ng at the
highest dose examined (3.6 x 10(9) plaque-forming units). The injection of
200 micrograms of plasmid DNA (pRSVL) produced levels of luciferase
comparable to 1.8 x 10(8) plaque-forming units of recombinant Ad5; however,
when normalized to the number of genes injected, the adenovirus was 140,000
times more efficient than plasmid DNA. Histochemical analysis of
beta-galactosidase activity produced by a second Ad5 vector demonstrated
that nearly all (> 95%) of the stained cells were cardiomyocytes and
that the percentage of cardiomyocytes infected by the virus could be quite
high in microscopic regions adjacent to the needle track (up to 75% in
fields of 60 to 70 cells); however, Ad5-infected cells were rarely observed
farther than 5 mm from the injection site. Furthermore, the Ad5 vector
induced pronounced leukocytic infiltration that was far in excess of that
seen after injection of vehicle alone. CONCLUSIONS--This study demonstrates
for the first time that direct intramyocardial injection of replication-
deficient adenovirus can program recombinant gene expression in the
cardiomyocytes of a large animal species with relevance to human
physiology. The efficiency of adenovirus-mediated gene transfer is far
superior to that of plasmid DNA injection, and this method appears to be
capable of producing more recombinant protein. However, the cell- mediated
immune response to the Ad5 vector and the limited distribution of reporter
gene expression suggest that less immunogenic recombinant vectors and more
homogeneous administration methods will be required before Ad5 vectors can
be successfully used for phenotypic modulation.
ARTICLES
Direct in vivo gene transfer into porcine myocardium using replication- deficient adenoviral vectors
Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
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