Biology of E1-deleted adenovirus vectors in nonhuman primate muscle.
Adenovirus vectors have been studied as vehicles for gene transfer to skeletal muscle, an attractive target for gene therapies for inherited and acquired diseases. In this setting, immune responses to viral proteins and/or transgene products cause inflammation and lead to loss of transgene expression. A few studies in murine models have suggested that the destructive cell-mediated immune response to virally encoded proteins of E1-deleted adenovirus may not contribute to the elimination of transgene-expressing cells. However, the impact of immune responses following intramuscular administration of adenovirus vectors on transgene stability has not been elucidated in larger animal models such as nonhuman primates. Here we demonstrate that intramuscular administration of E1-deleted adenovirus vector expressing rhesus monkey erythropoietin or growth hormone to rhesus monkeys results in generation of a Th1-dependent cytotoxic T-cell response to adenovirus proteins. Transgene expression dropped significantly over time but was still detectable in some animals after 6 months. Systemic levels of adenovirus-specific neutralizing antibodies were generated, which blocked vector readministration. These studies indicate that the cellular and humoral immune response generated to adenovirus proteins, in the context of transgenes encoding self-proteins, hinders long-term transgene expression and readministration with first-generation vectors.
Zoltick
P W
PW
Institute for Human Gene Therapy, University of Pennsylvania, USA.
Chirmule
N
N
Schnell
M A
MA
Gao
G P
GP
Hughes
J V
JV
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D017498:Adenovirus E1 Proteins / Q000235:genetics*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D016207:Cytokines / Q000032:analysis; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D013006:Growth Hormone / Q000097:blood / Q000235:genetics; D007273:Injections, Intramuscular; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D009500:Neutralization Tests; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D017498:Adenovirus E1 Proteins; D000914:Antibodies, Viral; D016207:Cytokines; D004921:Erythropoietin; D013006:Growth Hormone