Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hum Gene Ther. 2011 Aug;22(8):985-97. doi: 10.1089/hum.2010.194. Epub 2011 Apr 11.
This study evaluated six adeno-associated viral (AAV) vectors expressing green fluorescent protein (GFP) from the liver-specific thyroid hormone-binding globulin (TBG) promoter made with novel capsids in canine liver-directed gene transfer. Studies in 1.5-month-old dogs, which were administered vector through a peripheral vein, showed that AAV8 capsid vectors had the most favorable performance profiles. Interestingly, the absolute levels of hepatocyte transduction achieved with AAV8 were lower in dogs compared with what had been achieved in mice and nonhuman primates. Additional studies were performed with AAV8 delivered into the hepatic artery in adult dogs, with higher doses of vector used to assess potential dose-limiting toxicities. These studies showed good transduction on day 7 in one dog that apparently was lost by day 28 in another dog through the generation of GFP-specific T cells. Each adult dog was carefully monitored for any hemodynamic changes associated with vector infusion. Both animals demonstrated mild to moderate hypotension and bradycardia, which appeared to be anesthesia-related, making it difficult to evaluate contributions of the vector.
本研究评估了六种腺相关病毒（AAV）载体，这些载体通过新型衣壳在犬肝定向基因转移中表达甲状腺激素结合球蛋白（TBG）启动子的绿色荧光蛋白（GFP）。在接受通过外周静脉给予载体的 1.5 个月大的狗中进行的研究表明，AAV8 衣壳载体具有最有利的性能特征。有趣的是，与在小鼠和非人灵长类动物中实现的水平相比，用 AAV8 实现的肝细胞转导的绝对水平较低。还在成年犬中进行了通过肝动脉给予 AAV8 的额外研究，使用更高剂量的载体来评估潜在的剂量限制毒性。这些研究显示在一只狗中在第 7 天具有良好的转导，而在另一只狗中通过 GFP 特异性 T 细胞的产生在第 28 天似乎丢失。每只成年狗都被仔细监测与载体输注相关的任何血液动力学变化。两只动物都表现出轻度至中度低血压和心动过缓，这似乎与麻醉有关，使得难以评估载体的贡献。
