Stratford-Perricaudet L D, Levrero M, Chasse J F, Perricaudet M, Briand P
Laboratoire de Génétique des Virus Oncogènes, Institut Gustave-Roussy, Villejuif, France.
Hum Gene Ther. 1990 Fall;1(3):241-56. doi: 10.1089/hum.1990.1.3-241.
Mutant mice of the Spf-ash strain have an inherited defect in ornithine transcarbamylase (OTC) protein synthesis, and were used to ascertain the potential of recombinant adenoviruses for introducing and expressing the normal gene lacking in these mice. These OTC mutant mice are characterized by a reduction in the amount of OTC activity, resulting in hyperammonemia, pronounced orotic aciduria, growth retardation, and sparse fur until weaning. A recombinant adenovirus that harbors the rat OTC cDNA under the control of the viral major late promoter (MLP) was constructed and injected into such newborn mice. The effect of the virus was analyzed by monitoring the hepatic OTC enzyme during several months after the injection. An increase in OTC activity was detected and was accompanied by a diminution of orotic acid in the urine. The observation of MLP-OTC mRNA transcripts over 1 year following the injection attests to the relatively long-term presence of the transferred gene. In those mice showing the greatest OTC activity, a normalization of the fur was also observed. The experiments reported here document the feasibility of using adenovirus for the direct delivery in vivo of a gene to restore an impaired metabolism.
Spf-ash品系的突变小鼠在鸟氨酸转氨甲酰酶（OTC）蛋白合成方面存在遗传性缺陷，被用于确定重组腺病毒导入并表达这些小鼠所缺乏的正常基因的潜力。这些OTC突变小鼠的特征是OTC活性降低，导致高氨血症、明显的乳清酸尿、生长迟缓以及断奶前毛发稀疏。构建了一种在病毒主要晚期启动子（MLP）控制下携带大鼠OTC cDNA的重组腺病毒，并将其注射到此类新生小鼠体内。通过在注射后的几个月内监测肝脏OTC酶来分析病毒的作用。检测到OTC活性增加，同时尿液中乳清酸减少。注射后1年多对MLP-OTC mRNA转录本的观察证明了转移基因的相对长期存在。在那些显示出最高OTC活性的小鼠中，还观察到毛发恢复正常。此处报道的实验证明了使用腺病毒在体内直接递送基因以恢复受损代谢的可行性。
