Translational Pharmacokinetics and Pharmacodynamics of a Cationic mRNA-Lipid Nanoparticle from Mice to Non-Human Primates

In a recent study, researchers have successfully developed a cationic lipid nanoparticle (LNP) that shows promise for mRNA delivery to specific organs in animals. This type of nanoparticle has the potential to selectively target the pulmonary endothelium, which offers a unique advantage for extrahepatic mRNA delivery. However, previous studies have highlighted the challenges associated with the use of cationic LNPs, such as infusion-related immune reactions and activation of the innate immune system, often resulting in transient complement activation.

This case study focuses on the discovery and advancement of a selected cationic LNP in non-human primates (NHPs) for initial pharmacokinetic assessment and evaluation of any potential immunostimulatory side effects. The researchers demonstrate that the surface charge of the LNP plays a crucial role in the selective expression of reporter mRNAs within the body.

In this study, they formulated an mRNA encoding the Tie2 agonist COMP-Angl with the LNP002 and conducted pharmacokinetic and pharmacodynamic readouts in two independent non-human primate studies.

One significant finding from this study is the ability to abrogate dose-dependent transient complement activation by extending the infusion time. Additionally, the researchers identified the blood-borne pharmacodynamic biomarker PDGFB as an indicator of Tie2-signalling in healthy pulmonary endothelium in vivo. This biomarker was discovered through single-cell sequencing and cluster-alignment of downstream effector genes, revealing a spatial profile that matches the delivered mRNA.

This breakthrough opens up new possibilities for the development of targeted mRNA therapies in the future.