Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo.
Cytomegalovirus (CMV) promoter is often present in recombinant adenovirus vectors (AdVs) suitable for gene therapy, ensuring high levels of transgene production in a wide range of hosts. Despite this characteristic, the presence of the AdV genome in target cells and tissues typically lasts longer than transgene production that may be rapidly extincted by ill-defined silencing mechanisms. In the present article, it is reported that transcriptionally active drugs, retinoic acid (RA) and histone deacetylase inhibitor trichostatin A (TSA), enhance AdV transgene expression in infected cells and tissues. The association of RA and TSA increased more than seven-fold above control the activity of AdVs encoding for LacZ or VEGF165. This effect was, at least in part, mediated by the direct activation of retinoic acid receptors. Finally, administration of RA and TSA alone at days 0 and 5 after infection prolonged transgene production up to 21 days after infection versus 6-8 days in untreated controls. These results indicate that transcriptionally active drugs improve AdV function and may represent a novel strategy to more efficiently design AdVs for gene therapy interventions.
Gaetano
C
C
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Catalano
A
A
Palumbo
R
R
Illi
B
B
Orlando
G
G
Ventoruzzo
G
G
Serino
F
F
Capogrossi
M C
MC
D000256:Adenoviridae / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors / Q000008:administration & dosage*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007763:Lac Operon; D008222:Lymphokines / Q000235:genetics; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D022701:Virosomes
D016228:Endothelial Growth Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008222:Lymphokines; D018168:Receptors, Retinoic Acid; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D022701:Virosomes; C012589:trichostatin A; D014212:Tretinoin