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

By S. Sabnis, E. Kumarasinghe, Timothy Salerno, C. Mihai, T. Ketova, Joe J. Senn, A. Lynn, A. Bulychev, I. McFadyen, Joyce Chan and 3 more. Molecular Therapy, 2018

700 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/47b0e37860922fc14fc3cc6a8a8804f4e1af8b7c

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Citations in the corpus

The role of lipid components in lipid nanoparticles for vaccines and gene therapy (2022, positive): “Interestingly, while MC3 is not completely biodegradable and metabolites persist in rats and non-human primates [48], the doses required for clinical application show no evidence of toxicity [3].”
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. (2019, positive): “33,40,44 Expression of hEPO could be sustained for over a month when dosed weekly, with a peak expression between 6 and 12 h after LNP administration.”
Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines (2019, positive): “To assess and compare the local tolerability of the different ioniz-able lipid LNPs, we administered 0.01 mg or 0.1 mg mRNA expressing prM-E from the Zika virus formulated in either MC3, lipid H, lipid M, lipid P, lipid Q, or lipid N in Sprague-Dawley rats IM.”