PDF(Pubmed)
Abstract：
Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period.
摘要：
丙酸血症是一种罕见的疾病，由丙酰辅酶A羧化酶α或β（PCCA或PCCB）亚基的缺陷引起，导致有毒代谢物的积累和复发，威胁生命的代谢失代偿事件。在这里，我们报告了对人类首创的中期分析，阶段1/2，开放标签，剂量优化研究和评估mRNA-3927的安全性和有效性的扩展研究，这是一种编码PCCA和PCCB的双重mRNA疗法。截至2023年5月31日，在5个剂量队列中招募了16名参与者。16名参与者中有12名完成了剂量优化研究并参加了扩展研究。在总共15.69人年的治疗中，总共施用了346次静脉内剂量的mRNA-3927。没有发生剂量限制性毒性。16名参与者中有15名（93.8%）报告了因治疗引起的不良事件。初步分析表明，随着剂量增加，mRNA-3927的暴露量增加，在12个月治疗前报告代谢失代偿事件的8名参与者中，代谢失代偿事件的风险降低了70％。
