LAUSR

Lipid nanoparticles (LNPs) are clinically proven to successfully deliver both small interfering RNA (siRNA) therapeutics and larger mRNA payloads for prophylactic vaccine applications. Non-human primates (NHPs) are generally considered to be the most predictive of human responses. However, for ethical and economic reasons, LNP compositions have historically been optimized in rodents. It has been difficult to translate LNP potency data from rodents to NHPs for intravenously (IV) administered products in particular. This presents a major challenge for preclinical drug development. We sought to investigate LNP parameters that have historically been optimized in rodents and found that seemingly innocuous changes result in large potency differences between species. For example, we discovered that the ideal particle size for NHPs (50-60 nm) is smaller than for rodents (70-80 nm). Surface chemistry requirements are also different, with almost double the amount of polyethylene glycol (PEG)-conjugated lipid needed for maximal potency in NHPs. By optimizing these two parameters, we gained approximately 8-fold increase in protein expression from intravenously administered mRNA-LNP in NHP. The optimized formulations were well tolerated when administered repeatedly with no loss of potency. This advancement enables the design of optimal LNP products for clinical development. This article is protected by copyright. All rights reserved.