Moderna Therapeutics, 200 Technology Square, Cambridge, MA 02139, USA.
Moderna Therapeutics, 200 Technology Square, Cambridge, MA 02139, USA.
Mol Ther. 2018 Jun 6;26(6):1509-1519. doi: 10.1016/j.ymthe.2018.03.010. Epub 2018 Mar 14.
The success of mRNA-based therapies depends on the availability of a safe and efficient delivery vehicle. Lipid nanoparticles have been identified as a viable option. However, there are concerns whether an acceptable tolerability profile for chronic dosing can be achieved. The efficiency and tolerability of lipid nanoparticles has been attributed to the amino lipid. Therefore, we developed a new series of amino lipids that address this concern. Clear structure-activity relationships were developed that resulted in a new amino lipid that affords efficient mRNA delivery in rodent and primate models with optimal pharmacokinetics. A 1-month toxicology evaluation in rat and non-human primate demonstrated no adverse events with the new lipid nanoparticle system. Mechanistic studies demonstrate that the improved efficiency can be attributed to increased endosomal escape. This effort has resulted in the first example of the ability to safely repeat dose mRNA-containing lipid nanoparticles in non-human primate at therapeutically relevant levels.
mRNA 疗法的成功取决于安全有效的递药载体。脂质纳米粒被认为是一种可行的选择。但是，人们担心是否可以实现可接受的慢性给药耐受性。脂质纳米粒的效率和耐受性归因于氨基脂质。因此，我们开发了一系列新的氨基脂质来解决这个问题。明确的构效关系研究产生了一种新的氨基脂质，它在啮齿动物和灵长类动物模型中提供了高效的 mRNA 递药，具有最佳的药代动力学。在大鼠和非人类灵长类动物中进行的 1 个月毒理学评价表明，新型脂质纳米粒系统没有不良事件。机制研究表明，效率的提高可归因于内体逃逸的增加。这项工作首次证明，能够在非人类灵长类动物中以治疗相关水平安全地重复给予含有 mRNA 的脂质纳米粒。
