Kozarsky K F, Jooss K, Donahee M, Strauss J F, Wilson J M
Institute for Human Gene Therapy, Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, USA.
Nat Genet. 1996 May;13(1):54-62. doi: 10.1038/ng0596-54.
Liver directed gene transfer with adenoviral vectors is being considered for the treatment of several metabolic diseases, including familial hypercholesterolaemia (FH). Gene replacement therapy of human low density lipoprotein (LDL) receptor gene into the murine model of FH transiently corrected the dyslipidaemia; however, humoral and cellular immune responses to LDL receptor developed--possibly contributing to the associated hepatitis and extinguishing of transgene expression. We evaluated an alternative strategy of ectopic expression in the liver of the very low density lipoprotein (VLDL) receptor, which is homologous to the LDL receptor but has a different pattern of expression. Infusion of recombinant adenoviruses containing the VLDL receptor gene corrected the dsylipidaemia in the FH mouse and circumvented immune responses to the transgene leading to a more prolonged metabolic correction.
腺病毒载体介导的肝脏靶向基因转移正被考虑用于治疗包括家族性高胆固醇血症（FH）在内的多种代谢性疾病。将人类低密度脂蛋白（LDL）受体基因替换疗法应用于FH小鼠模型，可短暂纠正血脂异常；然而，机体对LDL受体产生了体液免疫和细胞免疫反应，这可能导致了相关肝炎以及转基因表达的消失。我们评估了一种替代策略，即在肝脏中异位表达极低密度脂蛋白（VLDL）受体，该受体与LDL受体同源，但表达模式不同。输注含有VLDL受体基因的重组腺病毒可纠正FH小鼠的血脂异常，并规避对转基因的免疫反应，从而实现更持久的代谢纠正。
