Gang Xuan, Liu Fei, Mao Jianhua
Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Front Pediatr. 2023 Jan 10;10:1052625. doi: 10.3389/fped.2022.1052625. eCollection 2022.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) defects encoded by the AGXT gene increase oxalate production, resulting in nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. Traditional pharmacological treatments for PH1 are limited. At present, the treatment direction of PH1 is mainly targeted therapy which refer to a method that targeting the liver to block the pathway of the production of oxalate. Lumasiran (OxlumoTM, developed by Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent, is the first drug approved for the treatment of PH1, which was officially approved by the US Food and Drug Administration and the European Union in November 2020. It is also the only drug that has been shown to decrease harmful oxalate. Currently, there are 5 keys completed and ongoing clinical trials of lumasiran in PH1. Through the three phase III trials that completed the primary analysis period, lumasiran has been shown to be effective in reducing oxalate levels in urine and plasma in different age groups, such as children, adults, and patients with advanced kidney disease, including those on hemodialysis. In addition to clinical trials, cases of lumasiran treatment for PH1 have been reported in small infants, twin infants, and children diagnosed with PH1 after kidney transplantation. These reports confirm the effectiveness and safety of lumasiran. All adverse events were of mild to moderate severity, with the most common being mild, transient injection-site reactions. No deaths or severe adverse events were reported. This article reviews PH1 and lumasiran which is the only approved therapeutic drug, and provide new options and hope for the treatment of PH1.
1型原发性高草酸尿症（PH1）是一种罕见的常染色体隐性遗传病，由AGXT基因突变引起。AGXT基因编码的肝脏过氧化物酶体酶丙氨酸乙醛酸转氨酶（AGT）缺陷会增加草酸盐的产生，导致肾钙质沉着、肾结石、慢性肾病和肾衰竭。PH1的传统药物治疗有限。目前，PH1的治疗方向主要是靶向治疗，即一种针对肝脏阻断草酸盐产生途径的方法。鲁马西拉（OxlumoTM，由Alnylam制药公司开发）是一种研究性RNA干扰（RNAi）治疗药物，是首个被批准用于治疗PH1的药物，于2020年11月获得美国食品药品监督管理局和欧盟的正式批准。它也是唯一一种已被证明可降低有害草酸盐的药物。目前，有5项关于鲁马西拉治疗PH1的关键临床试验已完成或正在进行。通过完成主要分析期的三项III期试验，已证明鲁马西拉在降低不同年龄组（如儿童、成人和晚期肾病患者，包括接受血液透析的患者）尿液和血浆中的草酸盐水平方面有效。除了临床试验外，还报告了鲁马西拉治疗小婴儿、双胞胎婴儿以及肾移植后被诊断为PH1的儿童的病例。这些报告证实了鲁马西拉的有效性和安全性。所有不良事件的严重程度均为轻度至中度，最常见的是轻度、短暂的注射部位反应。未报告死亡或严重不良事件。本文综述了PH1和唯一获批的治疗药物鲁马西拉，为PH1的治疗提供了新的选择和希望。
