Adenovirus-mediated beta-galactosidase gene delivery to the liver leads to protein deposition in kidney glomeruli.
Adenovirus-mediated beta-galactosidase gene delivery to the liver leads to protein deposition in kidney glomeruli.
复制标题
腺病毒介导的β-半乳糖苷酶基因递送至肝脏导致蛋白质沉积在肾小球中。
DOI：
10.1038/ki.1997.421
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发表时间：
1997
影响因子：
19.6
通讯作者：
Sukhatme,VP
中科院分区：
文献类型：
--
作者：
Zhu,G;Nicolson,AG;Zheng,XX;Strom,TB;Sukhatme,VP
腺病毒介导的β-半乳糖苷酶基因传递到肝脏导致肾小球中的蛋白质沉积。肾脏的许多细胞类型，精确排列，允许这个器官执行其复杂的生理功能。然而，这种结构的复杂性使得基因转移到肾脏变得困难。将治疗性蛋白质输送到肾脏的一种方法是将基因转移到非肾组织。如果蛋白质具有适当的分子特性，那么释放到血液循环中的蛋白质可能会导致在肾脏中的沉积。在这项研究中，我们发现肠外注射携带β-半乳糖苷酶基因的复制缺陷腺病毒导致肝细胞中β-半乳糖苷酶基因的强烈表达。作为对转导肝细胞的免疫攻击的结果，来自这些细胞的β-半乳糖苷酶蛋白被释放到循环中，运输，并几乎完全沉积在肾小球中。在两个肾脏中观察到强烈的β-半乳糖苷酶活性，在病毒给药后两周达到高峰，同时伴有β-半乳糖苷酶阳性肝细胞的丢失。与我们的蛋白质转移假设一致，在肾小球中检测到无β-半乳糖苷酶mRNA。此外，系统给药的蛋白质产生类似的肾小球β-半乳糖苷酶活性。最后，小鼠CTLA4 Ig（一种T细胞活化的免疫调节剂）与腺病毒共同给药可保护感染的肝细胞，并显著降低肾小球β-半乳糖苷酶活性。总的来说，这些发现表明，一种治疗性蛋白可以“靶向”肾小球，利用肝脏作为基因转移器官。
Adenovirus-mediatedβ-galactosidase gene delivery to the liver leads to protein deposition in kidney glomeruli.The many cell types of the kidney, precisely arranged, allow this organ to perform its complex physiologic functions. However, this architectural complexity makes gene transfer into the kidney difficult. One approach to delivering a therapeutic protein to the kidney is to transfer a gene to a non-renal tissue. Release of the protein into the circulation might then result in deposition in the kidney, if the protein has the appropriate molecular properties. In this study, we found that parenterally administered replication deficient adenovirus carrying theβ-galactosidase gene resulted in intenseβ-galactosidase gene expression in hepatocytes. As a result of immune attack on transduced hepatocytes,β-galactosidase protein from these cells is released into the circulation, transported, and deposited almost exclusively in kidney glomeruli. Intenseβ-galactosidase activity was noted in both kidneys with a peak at two weeks following viral administration, concurrent with loss ofβ-galactosidase positive hepatocytes. Consistent with our hypothesis of protein transfer, noβ-galactosidase mRNA was detected in glomeruli. Moreover, systemically administered protein generated similar glomerularβ-galactosidase activity. Finally, co-administration of murine CTLA4 Ig, an immunomodulator of T cell activation, with the adenovirus protected infected hepatocytes and markedly diminished glomerularβ-galactosidase activity. Collectively, these findings suggest that a therapeutic protein can be “targeted” to the renal glomerulus, utilizing the liver as a gene transfer organ.