A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy

摘要 最近新冠肺炎信使核糖核酸疫苗的临床成功引发了人们对信使核糖核酸疗法的巨大兴趣 广泛的生物医学应用，包括蛋白质替代疗法。然而，一个独特的挑战 与信使核糖核酸治疗相关的是由于其相对较短的半衰期而处理的暂时性疗效。当前 包括FDA批准的脂质纳米粒(LNPs)在内的纳米粒可以显著提高mRNA翻译水平 效率，但这些信使核糖核酸在体内表达蛋白质的持续时间通常很短(仅限于少数 天)，因此需要频繁地重新给药。这个项目的主要目标是推动一种新的变革性 LNP技术使长效mRNA替代疗法能够治疗与基因缺失相关的遗传疾病 一种特定蛋白质的功能。在我们最近的研究中，我们开发了新一代LNPs并进行了 与FDA批准的基准LNP制剂在体内外的面对面比较 可电离的脂类。我们观察到在体外和体内模型蛋白表达的持续时间显著增加。 由我们新的信使核糖核酸决定。初步的安全性研究表明，我们的mRNALNPs在没有 活体内可观察到的不良事件。通过我们的长效信使核糖核酸的概念验证演示，这 该项目旨在i)进一步优化mRNA LNP技术，以实现更长期、高水平的蛋白质表达，以及 Ii)以血友病A为模型疾病，严格验证这一变革性的信使核糖核酸传递平台。我们 预计随着在正常和血友病A小鼠中的成功验证，这个长效mRNA LNP平台 可以很容易地转移到血友病的临床测试中，并扩展到需要 恢复正常的蛋白质功能。

ABSTRACT Recent clinical success of mRNA vaccines for COVID-19 has sparked enormous interest in mRNA therapy for a wide range of biomedical applications including protein replacement therapy. However, one unique challenge associated with mRNA therapy is dealing with the transient efficacy due to its relatively short half-life. Current nanoparticles including FDA-approved lipid nanoparticles (LNPs) could significantly improve mRNA translation efficiency, but the duration of in vivo protein expression by these mRNA NPs is generally short (limited to a few days), thus requiring frequent re-dosing. The main objective of this project is to advance a new transformative LNP technology enabling long-acting mRNA replacement therapy of genetic disorders associated with loss of function of a particular protein. In our recent studies, we developed a new generation of LNPs and performed the head-to-head comparison in vitro and in vivo to the benchmark LNP formulations composed of FDA-approved ionizable lipids. We observed a dramatic increase of the duration of model protein expression in vitro and in vivo by our new mRNA LNPs. Preliminary safety studies showed that our mRNA LNPs were well tolerated without observable adverse events in vivo. With the proof-of-concept demonstration of our long-acting mRNA LNPs, this project aims to i) further optimize the mRNA LNP technology for longer-term, high level protein expression, and ii) rigorously validate this transformative mRNA delivery platform using hemophilia A as a model disease. We expect that with successful validation in normal and hemophilia A mice, this long-acting mRNA LNP platform could be readily moved into clinical testing for hemophilia and expanded to other genetic diseases that require restoration of normal protein functions.