In vivo timing of onset of transgene expression following adenoviral-mediated gene transfer.
Recombinant adenoviruses are efficient gene transfer vehicles that could be used for treatment of acute diseases. However, the time required for adenoviruses to produce physiologically relevant levels of transgene in vivo is unknown. To address this question rat lungs were infected with an E1a(-)/E3a(-) adenovirus that contains an hCMV-driven human beta(2)-adrenergic receptor (beta(2)AR) cDNA. Human beta(2)AR message and protein expression were noted 2-4 h postinfection without evidence of pseudotransduction. beta(2)AR function (cAMP production) was increased at 6 h postinfection. To determine when beta(2)AR gene transfer affects downstream catecholamine-sensitive pathways, we measured lung Na,K-ATPase expression and alveolar fluid clearance (AFC). beta(2)AR gene transfer increased Na,K-ATPase number by 80% at 6 h, and AFC by 20% at 8 h postinfection. These data indicate that recombinant adenoviruses can produce physiologically significant levels of transgene within hours of infection and that they may be suitable for gene therapies for acute, rapidly progressive diseases.
Dumasius
Vidas
V
Section of Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, Evanston, IL 60201, USA.
Jameel
Mohammed
M
Burhop
James
J
Meng
Fan Jing
FJ
Welch
Lynn C
LC
Mutlu G
Gökhan M
GM
Factor
Phillip
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes
D018343:Receptors, Adrenergic, beta-2