Abstract
Top of pageAbstract Vectors containing group B adenovirus (Ad) fibers have been shown to efficiently transduce gene therapy targets that are refractory to infection with standard Ad serotype 5 (Ad5) vectors, including malignant tumor cells, hematopoietic stem cells, and dendritic cells. Preliminary studies in mice indicate that B-group fiber containing Ads do not efficiently transduce most organs and cause less acute toxicity than Ad5 vectors after intravenous injection. However, biodistribution and safety studies in mice are of limited value because the mouse analogue of the B-group Ad receptor, CD46, is expressed only in the testis, while in humans, CD46 is expressed on all nucleated cells. Unlike mice, baboons have CD46 expression patterns and levels that closely mimic those in humans. We conducted a biodistribution and toxicity study of group B Ad vectors in baboons. Animals received intravenous injection of PBS, a standard Ad5 vector, or chimeric vectors containing B-group Ad11 or Ad35 fibers (Ad5/35 or Ad5/11) at dose of 2|[times]|1012 vp/kg and biodistribution and safety was analyzed over 3 days. Analysis of Ad5/35 and Ad5/11 vector genome distribution by quantitative PCR revealed uptake into most tissues at levels 1-3 orders of magnitude below that of Ad5. Significant Ad5/35 and Ad5/11-mediated transgene (b-galactosidase) expression was only seen in the marginal zone of splenic follicles. Compared to the animal that received the Ad5 vector, all animals injected with B-group fiber containing Ad vectors had lower elevations in serum pro-inflammatory cytokine levels. Gross and histopathology were normal in animals that received B-group Ad fiber containing Ads, in contrast to the Ad5 infused animal which showed widespread endothelial damage and inflammation (which is in agreement with studies performed by others). In a further study, a chimeric Ad5/35 vector carrying pro-apoptotic TRAIL and Ad E1A genes under tumor-specific regulation was well tolerated in a 30 day toxicity study. No major clinical, serologic or pathologic abnormalities were noticed in this animal. Overall, this study suggests that Ad vectors possessing B-group Ad fibers have a better safety profile after intravenous injection than conventional Ad5-based vectors. This makes them potential candidates for gene therapy, for example in treatment of metastatic cancer or cardiovascular diseases.
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