A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy

摘要 最近针对COVID-19的mRNA疫苗的临床成功引发了对mRNA疗法的极大兴趣， 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mRNA治疗相关的一个重要问题是处理由于其相对较短的半衰期而引起的瞬时功效。电流 包括FDA批准的脂质纳米颗粒（LNPs）在内的纳米颗粒可显著提高mRNA翻译 但是这些mRNA NP的体内蛋白表达的持续时间通常很短（限于少数几个 天），因此需要频繁重新给药。该项目的主要目标是推动一个新的变革性的 LNP技术使与基因缺失相关的遗传性疾病的长效mRNA替代疗法成为可能 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LNP，并进行了 在体外和体内与基准LNP制剂进行头对头比较， 可电离脂质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 我们新的mRNA LNP。初步的安全性研究表明，我们的mRNA LNP耐受性良好， 体内可观察到的不良事件。随着我们的长效mRNA LNP的概念验证， 该项目旨在i）进一步优化mRNA LNP技术，以实现长期、高水平的蛋白表达， ii）使用血友病A作为模型疾病严格验证这种变革性mRNA递送平台。我们 预期随着在正常和血友病A小鼠中的成功验证， 可以很容易地转移到血友病的临床测试，并扩展到其他遗传疾病， 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.