New therapeutics for primary hyperoxaluria type 1.
New therapeutics for primary hyperoxaluria type 1.
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DOI：
10.1097/mnh.0000000000000790
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发表时间：
2022-07-01
影响因子：
3.2
通讯作者：
Lieske, John C.
中科院分区：
文献类型：
--
作者：
Dejban, Pegah;Lieske, John C.
原发性高尿酸1型（PH 1）是一种罕见的遗传性疾病，可导致肝脏草酸盐过度生成，并经常导致肾钙质沉着症、肾结石、慢性肾脏疾病和肾衰竭。该综述的目的是提供目前用于治疗PH 1的新兴疗法的更新。使用核糖核酸干扰（RNAi）治疗靶向肝脏阻断关键酶的生产沿着产生草酸的途径是一种有前途的方法。现有证据支持Lumasiran（靶向乙醇酸氧化酶）和Nedosiran（靶向肝乳酸脱氢酶（LDHa））减少PH 1中尿草酸排泄的疗效。替代方法的有效性，包括stiripentol（一种抗惊厥药物，也针对LDHa），镧（一种潜在的胃肠道草酸盐结合剂），和Oxalpectin formigenes（一种可以在胃肠道内降解草酸盐的细菌，也可能增加其从血液中的分泌）也在研究中。包括成簇的规则间隔短回文重复序列/Cas9（CRISPR/Cas9）在内的基因编辑工具也作为潜在的PH 1治疗剂处于临床前研究中。新的治疗方法可以降低PH 1患者的血浆草酸盐浓度和尿草酸盐排泄。因此，这些方法可能会减少对CLKT的需求，从而显著降低受影响患者的发病率和死亡率。
Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that causes hepatic overproduction of oxalate and, often, nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. The purpose of the review is to provide an update on current emerging therapies for treatment of PH1. Use of ribonucleic acid interference (RNAi) therapeutics that target the liver to block production of key enzymes along pathways that generate oxalate is a promising approach. Available evidence supports the efficacy of both Lumasiran (targeting glycolate oxidase) and Nedosiran (targeting hepatic lactate dehydrogenase (LDHa)) to reduce urinary oxalate excretion in PH1. The efficacy of alternative approaches including stiripentol (an anti-convulsant drug that also targets LDHa), lanthanum (a potential gastrointestinal oxalate binder), and Oxalobacter formigenes (a bacterium that can degrade oxalate within the gastrointestinal tract and may also increase its secretion from blood) are all also under study. Genetic editing tools including clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) are also in preclinical study as a potential PH1 therapeutic. Novel treatments can reduce the plasma oxalate concentration and urinary oxalate excretion in PH1 patients. Thus, it is possible these approaches will reduce the need for CLKT to significantly decrease the morbidity and mortality of affected patients.