This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the major challenges in the field of gene therapy is the development of efficient and safe gene delivery systems. Although adenoviruses are one of the most extensively studied viruses currently utilized for gene therapy applications, clinical use of these vectors has been limited due to their ability to elicit a strong immune response. This response can compromise the patient s health, limit the length of transgene expression and prohibit gene expression upon re-administration of the virus. Development of gutted , or helper-dependent, adenoviral (HD-Ad) vectors by removing all viral sequences has significantly reduced the toxicity associated with the virus, but the host response against capsid proteins can still induce severe side effects soon after administration of doses necessary for clinical treatment. This effect is not seen in rodent models commonly used in pre-clinical testing. These effects are, however, quite profound in non-human primates suggesting that this animal model is more suitable for predicting vector performance in the clinic. In these studies, baboons will be given either a low (5 x 1011 virus particles (vp/kg)) intermediate (3 x 1012 vp/kg) or high does (1 x 1013) of PEGylated adenovirus by intravenous injection. Animals receiving similar doses of unmodified virus from the same preparation will serve as controls. Blood samples will be taken prior to administration of virus and for a period of 4 days after administration for blood cell counts, blood chemistry and cytokine analysis sand measurement of anti-adenovirus antibodies. Animals will be euthanized four days after administration of the virus and all organs harvested for assessment of differences in whole-body distribution patterns between unmodified and PEGylated virus. Results from these studies could have significant impact on the use of adenovirus-mediated gene transfer in the clinic. They will also provide valuable preliminary data for additional pre-clinical testing of other modified viruses for the treatment of genetic disease.
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