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


Authors: S. Sabnis, E.S. Kumarasinghe, T. Salerno, C. Mihai, T. Ketova, J.J. Senn, A. Lynn, A. Bulychev, I. McFadyen, J. Chan, Ö. Almarsson, M.G. Stanton and K.E. Benenato

Journal: Molecular Therapy

DOI: 10.1016/j.ymthe.2018.03.010

Publication - Abstract

March 14, 2018

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.

Advanced Search

close
  • Publications
  • Application Notes
  • Posters
  • Workshops
  • Videos & Webinars
  • Articles
Search

Browse by Category

  • Application
    • Diagnostic and Imaging
    • Genetic Medicine
    • Hematology
    • Metabolic Disorders
    • Neuroscience
    • Oncology
    • Skeletal Disorders
    • Targeted Drug Delivery
    • Vaccines
    • Other Applications
    • Cell therapy
  • Formulation
    • Liposomes
    • Nucleic Acid Lipid Nanoparticles
    • Polymeric Nanoparticles
    • Other Formulations
  • Payload
    • DNA
    • microRNA
    • mRNA
    • siRNA
    • Small Molecule Drugs
    • Other Payloads


related content

Publication - Abstract

A High-throughput Galectin-9 Imaging Assay for Quantifying Nanoparticle Uptake, Endosomal Escape and Functional RNA Delivery

M.J. Munson, G. O'Driscoll, A.M. Silva, E. Lázaro-Ibáñez, A. Gallud, J.T. Wilson, A. Collén, E.K. Esbjörner and A. Sabirsh

RNA-based therapies have great potential to treat many undruggable human diseases. However, their efficacy, in particular for mRNA, remains hampered by poor cellular delivery and limited endosomal escape. Development and optimisation of delivery vectors, such as lipid nanoparticl...
Read More


Publication - Abstract

Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we e...
Read More


Sign Up and Stay Informed
Sign up today to automatically receive new Precision NanoSystems application notes, conference posters, relevant science publications, and webinar invites.