Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors

Nat Med. 1996 May;2(5):545-50. doi: 10.1038/nm0596-545.


The use of replication-defective adenoviruses (RDAd) for human gene therapy has been limited by host immune responses that result in transient recombinant gene expression in vivo. It remained unclear whether these immune responses were directed predominantly against viral proteins or, alternatively, against foreign transgene-encoded proteins. In this report, we have compared the stability of recombinant gene expression in adult immunocompetent mice following intramuscular (i.m.) injection with identical RDAd encoding self (murine) or foreign (human) erythropoietin. Our results demonstrate that immune responses direct against foreign transgene-encoded proteins are the major determinants of the stability of gene expression following i.m. injection of RDAd. Moreover, we demonstrate long-term recombinant gene expression in immunocompetent animals following a single i.m. injection of RDAd encoding a self protein. These findings are important for the design of future preclinical and clinical gene therapy trials.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / growth & development
  • Adenoviridae / immunology
  • Adenovirus E1 Proteins / genetics
  • Adenovirus E3 Proteins / genetics
  • Animals
  • Base Sequence
  • Erythropoietin / biosynthesis
  • Erythropoietin / genetics
  • Erythropoietin / immunology*
  • Gene Expression*
  • Genetic Therapy
  • Genetic Vectors / genetics*
  • Genetic Vectors / immunology
  • Humans
  • Injections, Intramuscular
  • Mice
  • Molecular Sequence Data
  • Recombinant Proteins / immunology
  • Species Specificity
  • Transgenes*


  • Adenovirus E1 Proteins
  • Adenovirus E3 Proteins
  • Recombinant Proteins
  • Erythropoietin