VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.
VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.
复制标题
DOI：
10.1096/fj.202101315r
复制
发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
多囊肾是一种常见的肾脏疾病，常染色体显性遗传。我们已经设计了一种治疗方法，基于通过使用VX-809（囊性纤维化跨膜调节剂运输和加工的调节剂）将囊肿表型从分泌逆转为吸收。我们的目标是在携带R3277 C人类突变的RC/RC小鼠中测试VX-809，以证明其治疗潜力。我们发现，到5个月大时，RC/RC小鼠有大囊肿和肾功能受损，但当在3至5个月或6至8个月大时用VX-809治疗时，两组的囊肿面积都减少了，这表明VX-809缩小了先前存在的囊肿。治疗2个月后，囊肿大小低于相同年龄的未治疗动物。我们的共定位研究证实，囊性纤维化跨膜传导调节因子（CFTR）主要存在于各年龄组未处理动物的顶膜，与其在Cl−分泌中的作用一致; VX-809处理后，CFTR的基底外侧膜共定位增加约4倍，同时其顶端共定位减少约2-3倍，表明VX-809改变了表型以有利于液体吸收。在正常肾脏的顶膜上发现的钠/氢交换器和上皮钠通道在囊肿中几乎不存在。VX-809使这两个水平恢复正常。HSP 27在RC/RC小鼠中高度表达，并且通过VX-809降低至正常。我们证明囊肿缩小、肾功能改善和吸收表型的产生都强烈支持VX-809作为ADPKD治疗的治疗潜力。我们在此显示，在人类ADPKD典型的缓慢进展的囊肿形成的动物模型中，VX-809减少了已经形成的囊肿的生长。与先前使用相同小鼠模型评价托伐普坦的实验相比，RC/RC小鼠模型中的作用幅度表明CFTR调节剂值得进一步开发作为ADPKD的治疗。
Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing. Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl− secretion; after VX-809 treatment, the basolateral membrane co-localization of CFTR increased ~4-fold, accompanied by a decrease of ~2–3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan indicates that CFTR modulators warrant further development as a treatment for ADPKD.