A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates

作者：Staci Sabnis, E. Sathyajith Kumarasinghe, Timothy Salerno, Cosmin Mihai, Tatiana Ketova, Joseph J. Senn, Andy Lynn, Alex Bulychev, Iain J. McFadyen, Joyce Chan, Örn Almarsson, Matthew G. Stanton, Kerry E. Benenato · 发表于：Molecular Therapy · 年份：2018 · DOI：10.1016/j.ymthe.2018.03.010 · 被引用次数：827 · 研究领域：RNA Interference and Gene Delivery、Advanced biosensing and bioanalysis techniques、Lipid Membrane Structure and Behavior

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.