Transient expression of genes transferred in vivo into heart using first-generation adenoviral vectors: role of the immune response.
Gene therapy for heart diseases requires availability of an efficient vector for gene transfer into myocardium. Recombinant adenovirus expressing the Escherichia coli beta-galactosidase (beta-Gal) gene was shown to infect rat cardiocytes efficiently in vivo. However, a time course of gene expression showed that transgene expression was maximal during the first week following injection, then declined and disappeared by day 21. An immunosuppressive treatment prolonged beta-Gal expression for at least 21 days. On the contrary, a preimmunization of the animals by two intraperitoneal injections of the vector led to a decreased transgene expression 48 hr after intramyocardial injection and to a barely detectable expression at the sixth day. Appearance of adenovirus neutralizing antibodies in preimmunized animals could have contributed to such a refractoriness to further adenoviral infection. Finally, a neonatal intrathymic injection of the vector was able to induce long-term LacZ expression for more than 2 months after heart injection, although neutralizing as well as anti-beta-Gal antibodies were detected in sera of the animals. These results indicate that an immune response against first-generation replication-defective adenoviral vectors is a major cause of transient transgene expression, a cellular response being most probably responsible for ablation of transgene expression in immunocompetent animals.
Gilgenkrantz
H
H
INSERM U.129, Institut Cochin de Génétique Moléculaire (ICGM), Université R. Descartes, Paris, France.
Duboc
D
D
Juillard
V
V
Couton
D
D
Pavirani
A
A
Guillet
J G
JG
Briand
P
P
Kahn
A
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D018014:Gene Transfer Techniques; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects / Q000821:virology; D007114:Immunization; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013950:Thymus Gland; D001616:beta-Galactosidase / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology
D000906:Antibodies; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D016572:Cyclosporine; D001616:beta-Galactosidase