Alnylam Pharmaceuticals, Cambridge, United States.
Blizard Institute and Institute for Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Elife. 2020 Mar 24;9:e54363. doi: 10.7554/eLife.54363.
By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of (expected ~1 in 30 million outbred people). (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.
通过对同源纯合人群进行测序，我们发现了一名成年女性，其体内的 （预期约为 300 万外婚人群中的 1 人）终身完全缺失。（乙醇酸氧化酶）沉默是 lumasiran 的作用机制，lumasiran 是一种用于治疗 1 型原发性高草酸尿症的研究性 RNA 干扰疗法。她的血浆乙醇酸水平是正常参考个体（n=67）上限的 12 倍，尿液乙醇酸水平是上限的 6 倍。血浆代谢组学和脂质组学（1871 种生物化学物质）显示有 18 种明显升高的生物化学物质（>5 sd 离群值与 n=25 名对照者相比），提示存在其他 HAO1 作用。与 lumasiran 的临床前和临床试验数据比较提示，她的乙醇酸氧化酶活性残留<2%。细胞系 p.Leu333SerfsTer4 表达显示 HAO1 蛋白水平和细胞内蛋白定位明显降低。在这名女性中，终身 缺失是安全的，且无临床表型，降低了治疗方法的风险，并为治疗机制提供了信息。从人类遗传变异的多样性中获取证据，可以促进药物开发。
