Chen S J, Tazelaar J, Moscioni A D, Wilson J M
Institute for Human Gene Therapy, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Ther. 2000 May;1(5 Pt 1):414-22. doi: 10.1006/mthe.2000.0065.
A murine model for hereditary tyrosinemia Type I (HTI) was evaluated for in vivo gene therapy with adeno-associated viral (AAV) vectors expressing the enzyme fumarylacetoacetate hydrolase. Transduction of a limited number of hepatocytes was accomplished following infusion of vector into the portal circulation. Corrected hepatocytes were expanded in vivo by withdrawing a drug which prevents the accumulation of toxic metabolites. The liver was eventually repopulated with hepatocytes harboring a functional and apparently integrated AAV provirus. Recipient animals regained normal liver function and architecture and the underlying metabolic derangements were normalized. After 9 months, vector-treated animals showed benign hepatomas, whereas in untreated animals areas of marked dysplasia were present within hepatomas.
对一种遗传性I型酪氨酸血症（HTI）的小鼠模型进行了评估，以研究使用表达延胡索酰乙酰乙酸水解酶的腺相关病毒（AAV）载体进行体内基因治疗。将载体注入门静脉循环后，实现了对有限数量肝细胞的转导。通过停用一种可防止有毒代谢物积累的药物，在体内使校正后的肝细胞得以扩增。肝脏最终被携带功能性且明显整合的AAV前病毒的肝细胞重新占据。受体动物恢复了正常的肝功能和结构，潜在的代谢紊乱也恢复正常。9个月后，接受载体治疗的动物出现了良性肝癌，而未治疗的动物肝癌内存在明显发育异常的区域。
