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
  • Blog Posts
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

Harnessing RNAi-Based Nanomedicines for Therapeutic Gene Silencing in B-cell Malignancies

S. Weinstein, I.A. Toker, R. Emmanuel, S. Ramishetti, I. Hazan-Halevy, D. Rosenblum, M. Goldsmith, A. Abraham, O. Benjamini, O. Bairey, P. Raanani, A. Nagler, J. Lieberman and D. Peer

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for ...

Read More


Publication - Abstract

Polymeric nanocapsules are versatile delivery systems with the capacity to load lipophilic drugs in their oily nucleus and hydrophilic drugs in their polymeric shell. The objective of this work was to expand the technological possibilities to prepare customized nanocapsules. Firs...
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.