Gao Guangping, Wang Qiang, Calcedo Roberto, Mays Lauren, Bell Peter, Wang Lili, Vandenberghe Luk H, Grant Rebecca, Sanmiguel Julio, Furth Emma E, Wilson James M
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
Hum Gene Ther. 2009 Sep;20(9):930-42. doi: 10.1089/hum.2009.060.
Gene transfer to murine liver with vectors based on novel adeno-associated virus (AAV) serotypes is efficient, stable, and safe even in the setting of antigenic transgene products. We undertook a study in cynomolgus macaques to evaluate the relevance of these findings to primates. The vectors were based on AAV serotype 7 and expressed green fluorescence protein (GFP) from the cytomegalovirus enhanced beta-actin promoter in both single-stranded and self-complementary genomes. Transduction efficiencies from the single-stranded vectors were similar to those observed in mice, although there was no advantage in primates with the self-complementary vectors. Primates elicited vibrant cytotoxic T cell responses to GFP that correlated with hepatitis and loss of transgene expression. There was no evidence of T cell activation in response to the AAV capsid. These studies indicate that under some conditions primates may activate more robust T cell responses to transgene products than is observed in mice.
即使在存在抗原性转基因产物的情况下，基于新型腺相关病毒（AAV）血清型的载体向小鼠肝脏进行基因转移也是高效、稳定且安全的。我们在食蟹猴中开展了一项研究，以评估这些发现与灵长类动物的相关性。这些载体基于AAV血清型7，并在单链和自我互补基因组中从巨细胞病毒增强型β-肌动蛋白启动子表达绿色荧光蛋白（GFP）。单链载体的转导效率与在小鼠中观察到的相似，尽管自我互补载体在灵长类动物中并无优势。灵长类动物对GFP引发了强烈的细胞毒性T细胞反应，这与肝炎及转基因表达丧失相关。没有证据表明T细胞会因AAV衣壳而激活。这些研究表明，在某些条件下，灵长类动物可能比在小鼠中观察到的情况对转基因产物激活更强有力的T细胞反应。
