ACTIVATION OF TRANSGENE EXPRESSION BY EARLY REGION-4 IS RESPONSIBLE FOR A HIGH-LEVEL OF PERSISTENT TRANSGENE EXPRESSION FROM ADENOVIRUS VECTORS IN-VIVO
De. Brough et al., ACTIVATION OF TRANSGENE EXPRESSION BY EARLY REGION-4 IS RESPONSIBLE FOR A HIGH-LEVEL OF PERSISTENT TRANSGENE EXPRESSION FROM ADENOVIRUS VECTORS IN-VIVO, Journal of virology, 71(12), 1997, pp. 9206-9213
The persistence of transgene expression has become a hallmark for aden
ovirus vector evaluation in vivo. Although not all therapeutic benefit
in gene therapy is reliant on long-term transgene expression, it is a
ssumed that the treatment of chronic diseases will require significant
persistence of expression, To understand the mechanisms involved in t
ransgene persistence, a number of adenovirus vectors were evaluated in
vivo in different strains of mice. Interestingly, the rate of vector
genome clearance was not altered by the complete deletion of early reg
ion 4 (E4) in our vectors. The GV11 (E1(-)E4(-)) vector genome cleared
with a similar kinetic profile as the GV10 (E1(-)) vector genome in i
mmunocompetent and immunocompromised mice, These results suggest that
the majority of adenovirus vector genomes are eliminated from transduc
ed tissue via a mechanism(s) independent of T cell, B-cell, and NK cel
l immune mechanisms. While the levels of persistence of transgene expr
ession in liver or lung transduced with GV10 and GV11 vectors expressi
ng beta-galactosidase, cystic fibrosis transmembrane conductance regul
ator, or secretory alkaline phosphatase were similar in immunocompeten
t mice, a marked difference was observed in immunocompromised animals.
Levels of transgene expression initially from both GV10 and GV11 vect
ors were the same. However, GV11 transgene expression correlated with
loss of vector genome, while GV10 transgene expression persisted at a
high level. Coadministration and readministration of GV10 vectors show
ed that E4 provided in trans could activate transgene expression from
the GV11 vector genome. While transgene expression activity per genome
from the GV10 vector is clearly activated, expression from a cytomega
lovirus promoter expression cassette in a GV11 vector appeared to be f
urther inactivated as a function of time. Understanding the molecular
mechanisms underlying these expression effects will be important for d
eveloping persistent adenovirus vectors for chronic applications.