Biology of E1-deleted adenovirus vectors in nonhuman primate muscle

Adenovirus vectors have been studied as vehicles for gene transfer to skele tal muscle, an attractive target for gene therapies for inherited and acqui red diseases. In this setting, immune responses to viral proteins and/or tr ansgene products cause inflammation and Lead to loss of transgene expressio n. A few studies in murine models have suggested that the destructive cell- mediated immune response to virally encoded proteins of E1-deleted adenovir us may not contribute to the elimination of transgene-expressing cells. How ever, the impact of immune responses following intramuscular administration of adenovirus vectors on transgene stability has not been elucidated in la rger animal models such as nonhuman primates. Here we demonstrate that intr amuscular administration of E1-deleted adenovirus vector expressing rhesus monkey erythropoietin or growth hormone to rhesus monkeys results in genera tion of a Th1-dependent cytotoxic T-cell response to adenovirus proteins. T ransgene expression dropped significantly over time but was still detectabl e in some animals after 6 months. Systemic levels of adenovirus-specific ne utralizing antibodies were generated, which blocked vector readministration , These studies indicate that the cellular and humoral immune response gene rated to adenovirus proteins, in the context of transgenes encoding self-pr oteins, hinders long-term transgene expression and readministration with fi rst-generation vectors.