The first clinical results for an RNA-editing oligonucleotide designed to correct a disease-causing single-base mutation in mRNA have been released. The company, Wave Life Sciences, says the agent WVE-006 restored more than 60% of wild-type functional protein in two individuals with the genetic disorder alpha-1 antitrypsin (ATT; encoded by SERPINA1) deficiency. ATT deficiency affects the liver owing to hepatic build-up of misfolded ATT protein, and causes lung disease owing to a lack of circulating ATT protein to protect the lungs from inflammatory damage. The RNA editor, potentially a first-in-class agent, acts by correcting a G-to-A mutation in the SERPINA1 Z allele transcript. Fifteen days after one dose, the patients’ functional AAT protein was almost seven micromolar, a level associated with a low risk of liver and lung disorders. AAT protein levels remained increased for two months in the patients.

“The level of mRNA editing … exceeded our expectations, and we expect [functional] AAT levels to continue to increase with repeat dosing,” said Wave’s president in the press release announcing the results. WVE-006 induces site-specific A-to-I changes in mRNA transcripts. Because the cell’s translation machinery reads I as G, ADAR editors correct pathogenic G-to-A mutations. WVE-006 is conjugated with N-acetylgalactosamine to facilitate hepatic delivery and phosphoryl guanidine backbone modifications improve efficiency. It is injected subcutaneously and does not use lipid nanoparticles for delivery. The molecule was part of a 2022 deal (worth $170 million upfront) with GSK, based in London, who will take over its development after the current trial has completed.

旨在纠正 mRNA 中致病单碱基突变的 RNA 编辑寡核苷酸的首次临床结果已经发布。Wave Life Sciences 公司表示，药物 WVE-006 在两名患有遗传疾病 α-1 抗胰蛋白酶 （ATT;由 SERPINA1 编码） 缺乏症的个体中恢复了 60% 以上的野生型功能蛋白。ATT 缺乏症是由于肝脏错误折叠的 ATT 蛋白积聚而影响肝脏，并且由于缺乏循环 ATT 蛋白来保护肺部免受炎症损伤而导致肺部疾病。RNA 编辑器可能是一流的代理，通过纠正 SERPINA1 Z 等位基因转录本中的 G 到 A 突变来发挥作用。一剂后 15 天，患者的功能性 AAT 蛋白几乎为 7 微摩尔，这一水平与肝脏和肺部疾病的低风险相关。患者的 AAT 蛋白水平持续升高两个月。

“mRNA 编辑的水平......超出了我们的预期，我们预计 [功能性] AAT 水平将随着重复给药而继续增加，“Wave 总裁在宣布结果的新闻稿中说。WVE-006 诱导 mRNA 转录本的位点特异性 A-to-I 变化。因为细胞的翻译机制将 I 读作 G，所以 ADAR 编辑者可以纠正致病性 G 到 A 突变。WVE-006 与 N-乙酰半乳糖胺偶联以促进肝脏递送，磷酸基胍骨架修饰可提高效率。它是皮下注射的，不使用脂质纳米颗粒进行输送。该分子是 2022 年与总部位于伦敦的 GSK 达成的交易（预估价值 1.7 亿美元）的一部分，GSK 将在当前试验完成后接管其开发。