Transient Expression of Genes Transferred in Vivo Into Heart Using First-Generation Adenoviral Vectors: Role of the Immune Response

Hum Gene Ther. 1995 Oct;6(10):1265-74. doi: 10.1089/hum.1995.6.10-1265.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Animals, Newborn
  • Antibodies / blood
  • Cyclosporine / pharmacology
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Gene Expression / immunology
  • Gene Transfer Techniques*
  • Heart / anatomy & histology
  • Heart / drug effects
  • Heart / virology
  • Immunization
  • Immunosuppressive Agents / pharmacology
  • Injections, Intraperitoneal
  • Myocardium* / immunology
  • Myocardium* / metabolism
  • Rats
  • Rats, Inbred Lew
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • Thymus Gland
  • beta-Galactosidase / genetics*
  • beta-Galactosidase / immunology
  • beta-Galactosidase / pharmacology

Substances

  • Antibodies
  • Immunosuppressive Agents
  • Recombinant Proteins
  • Cyclosporine
  • beta-Galactosidase