期刊
MOLECULAR THERAPY
卷 13, 期 1, 页码 77-87出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2005.08.017
关键词
novel AAVs; vector biology; NHP model for liver gene transfer; gene expression; molecular status of vector genome; preexisting immunity; safety profiles
资金
- NHLBI NIH HHS [P01 HL59407] Funding Source: Medline
- NIDDK NIH HHS [P30 DK47757] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL059407] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK047757] Funding Source: NIH RePORTER
Vectors based on adeno-associated viruses (AAVs) show promise for the treatment of genetic diseases. This study evaluates the biology of AAV-mediated gene transfer to liver in nonhuman primates (NHPs) using vectors based on AAV serotypes 2, 7, and 8. Transgenes encoding self-proteins were selected to minimize the confounding development of transgene-specific immune responses. These included the beta subunit of choriogonadotropic hormone (bCG) and erythropoietin (Epo), both derived from cDNAs from rhesus macaques. Experiments were performed with bCG in rhesus macaques and Epo in cynomolgus macaques. We demonstrated the previously untested hypothesis that preexisting immunity to a natural infection does substantially diminish the efficacy of gene transfer with a vector derived from an endogenous virus. Route of vector administration clearly has an impact on the development of immune responses to self-antigens. In general, efficiency of gene transfer to liver with AAV7 and 8 vectors was higher than what was achieved with AAV2, although a variety of host factors may influence this important parameter, such as preexisting immunity, gender, and transgene immunity.
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