Nat Commun:双mRNA疗法恢复丙酸血症的代谢功能

2020-10-24 haibei MedSci原创

最近,研究人员在Nature Communications发文,报告了一种酶替代方法来治疗PA。其使用两种信使RNA(mRNAs)(双mRNAs)编码人PCCA(hPCCA)和PCCB(hPCCB)。

目前,mRNA技术的最新进展已经改变了系统mRNA封装在脂质纳米颗粒(LNPs)中的前景,以产生治疗性的细胞内和分泌的蛋白质。mRNA技术的关键优势包括其瞬时,非整合的性质,并能够提供多个mRNA来编码复杂的多聚体蛋白。然而,外源性mRNA的长期疗效和安全性仍有待在临床前研究中进行全面评估。

丙酸血症/酸尿症(PA)是一种极其罕见的、危及生命的、由线粒体酶--丙酰基-CoA羧化酶(PCC)缺乏引起的遗传性代谢紊乱。PCC由6个α(PCCA)和6个β(PCCB)亚单位组成。其突变会导致丙酸代谢障碍和毒性代谢物的异常积累,包括主要疾病标志物2-甲基柠檬酸盐(2MC),3-羟基丙酸(3HP)和丙酰肉碱(C3)。通过这些代谢物和丙酰CoA(PCC的底物)抑制尿液生成也导致高氨血症。

最近,研究人员在Nature Communications发文,报告了一种酶替代方法来治疗PA。其使用两种信使RNA(mRNAs)(双mRNAs)编码人PCCA(hPCCA)和PCCB(hPCCB)。两条mRNA被组合封装在生物可降解的脂质纳米颗粒(LNPs)中,在肝脏中产生功能性PCC酶。

在患者成纤维细胞中,双mRNAs编码的蛋白在线粒体中定位,并产生较高的PCC酶活性,而单独的(PCCA或PCCB)mRNA治疗效果较差。

在PA的小鼠模型中,双mRNAs使小鼠体内氨正常化,效果类似于卡鲁米酸,一种在欧洲被批准用于治疗PA引起的高氨血症的药物。

在PA小鼠中3个月和6个月的长期重复剂量研究中,双mRNAs还能恢复肝脏中功能性PCC酶,从而以剂量依赖的方式减少原发疾病相关毒素。在这些研究中,双mRNAs的耐受性良好,无不良发现。

这些研究表明,mRNA技术具有慢性施用多个mRNA以产生大型复杂酶的潜力,并可适用于其他遗传性疾病。

 

原始出处:

Lei Jiang et al. Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia. Nature Communications (2020). 

 

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