Human Molecular Genetics, Vol 7, 1893-1900, Copyright © 1998 by Oxford University Press
R Kumar-Singh and DB Farber
First (DeltaE1/E3) and second (DeltaE1+DeltaE2/E3/E4) generation adenovirus
(Ad) vectors have been shown previously to be of limited use in the
treatment of human genetic diseases due to the induction of a host
cytotoxic T-cell mediated immune response against virally expressed genes.
In addition, a limited cloning capacity of approximately 8 kb does not
cater for the incorporation of large upstream sequences essential for
regulated tissue-specific expression or inclusion of multiple
gene-expression cassettes. In this study we have exploited our recently
developed Ad-based vector, the encapsidated adenovirus mini-chromosome
(EAM) from which all of the viral genes have been deleted. EAMs contain
only the inverted terminal repeats required for replication and five cis
-acting Ad encapsidation signals necessary for packaging. We have shown
previously that EAMs can efficiently transduce a variety of cell types in
vitro. In this study we demonstrate that EAMs can transduce and rescue
cells from the neurosensory retina in vivo. EAM-mediated delivery of the
beta subunit of cyclic GMP phosphodiesterase (PDE) cDNA to mice affected
with retinal degeneration (rd) allows prolonged transgene expression and
rescue of rod photoreceptor cells. RT-PCR analysis from the injected retina
indicates that transgene products are present for at least 18 weeks
post-injection. Both the alpha and beta subunits of PDE could be detected
up to 90 days postnatal in EAM-injected rd retina by western analysis. A
maximal PDE activity of 150 nm/min/mg was detected at 33 days postnatal.
Examination of outer nuclear thickness showed significant differences up to
12 weeks post-injection. These results demonstrate an improved level of
rescue over first-generation adenoviral vectors and suggest the possibility
of successful EAM- mediated treatment of some retinal diseases in humans.
ARTICLES
Encapsidated adenovirus mini-chromosome-mediated delivery of genes to the retina: application to the rescue of photoreceptor degeneration
Jules Stein Eye Institute, School of Medicine and Molecular Biology Institute, UCLA, 100 Stein Plaza, Room B243, Los Angeles, CA 90095- 7008, USA. rajendra@ucla.edu
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