Overturf K, Al-Dhalimy M, Tanguay R, Brantly M, Ou C N, Finegold M, Grompe M
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201, USA.
Nat Genet. 1996 Mar;12(3):266-73. doi: 10.1038/ng0396-266.
Current strategies for hepatic gene therapy are either quantitatively inefficient or suffer from lack of permanent gene expression. We have utilized an animal model of hereditary tyrosinaemia type I (HT1), a recessive liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH), to determine whether in vivo selection of corrected hepatocytes could improve the efficiency of liver gene transfer. As few as 1,000 transplanted wild-type hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections >90% of hepatocytes became FAH positive and liver function was restored to normal. Our results demonstrate that in vivo selection is a useful strategy for hepatic gene therapy and may lead to effective treatment of human HT1 by retroviral gene transfer.
目前用于肝脏基因治疗的策略要么在数量上效率低下，要么缺乏永久性基因表达。我们利用I型遗传性酪氨酸血症（HT1）的动物模型，这是一种由富马酰乙酰乙酸水解酶（FAH）缺乏引起的隐性肝脏疾病，来确定体内选择校正后的肝细胞是否能提高肝脏基因转移的效率。少至1000个移植的野生型肝细胞就能使突变肝脏重新增殖，证明了它们强大的竞争性生长优势。通过逆转录病毒基因转移在原位校正的突变肝细胞也得到了阳性选择。在通过多次注射逆转录病毒治疗的突变动物中，超过90%的肝细胞变为FAH阳性，肝功能恢复正常。我们的结果表明，体内选择是肝脏基因治疗的一种有用策略，可能会通过逆转录病毒基因转移有效治疗人类HT1。
