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

Abstract

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.

Adeno-associated virus–mediated gene transfer of endostatin inhibits angiogenesis and tumor growth in vivo

“…Adenovirus -based gene transfer induces inflammatory and immune responses that lead to loss of the transduced cell and result in transient gene expression and limited efficacy of repeated deliveries. 39 Even if the immune reactions could be minimized, the full potential for long -term expression is not realizable because the adenovirus cannot integrate. An alternative strategy, the use of the adeno -associated virus for endostatin gene transfer was explored in the present series of investigations.…”

Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates

“…The lack of immune response in C57BL/6 mice is not surprising since there are several reports in the literature regarding the varied immune response in this strain of mice to multiple antigens delivered by adenoviral vectors. [22][23][24][25] These results highlight the important influence of mouse haplotype on the generation of immune response against a foreign transgene.…”

Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

“…33 The drawback of this adenoviral vector is its immunogenicity, so that repetitive adenoviral DNA transfer to animals results in the elimination of its gene products. However, Tripathy et al 34 reported that the expression of endogenous proteins in animals lessens the development of their immunorejection. Kay et al 35 demonstrated, furthermore, the effect of CTLA4Ig, a costimulatory signal inhibitor between T lymphocytes and antigen-presenting cells.…”