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

Nucleic Acid Lipid Nanoparticles siRNA Other Applications
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.

limit search to this category
Advanced Search

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

Dec 15, 2016
Nanoscale

Dual-Functional Lipid-Like Nanoparticles for Delivery of mRNA and MRI Contrast Agents

X. Luo, B. Li, X. Zhang, W. Zhao, A. Bratasz, B. Deng, D.W. McComb and Y. Dong

Diagnostic and Imaging Nucleic Acid Lipid Nanoparticles mRNA

Multi-functional nanomaterials possess unique properties, facilitating both therapeutic and diagnostic applications among others. Herein, we developed dual-functional lipid-like nanoparticles for simultaneous delivery of mRNA and magnetic resonance...

Read More


Publication - Summary

Jan 19, 2016
Proceedings of the National Academy of Sciences

Modular Degradable Dendrimers Enable Small RNAs to Extend Survival in an Aggressive Liver Cancer Model

K. Zhou, L.H. Nguyen, J.B. Miller, Y. Yan, P. Kos, H. Xiong, L. Li, J. Hao, J.T. Minnig, H. Zhu and D.J. Siegwart

microRNA siRNA Polymeric Nanoparticles

Liver cancer is a deadly disease with limited intervention options. Tumour removal surgery and liver transplantation are extremely complicated and not always possible. Several small molecule drugs aimed to treat hepatocellular carcinoma (HCC) have ...

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.
Sign Up