Details

Autor(en) / Beteiligte

• Sabnis, Staci
• Kumarasinghe, E. Sathyajith
• Salerno, Timothy
• Mihai, Cosmin
• Ketova, Tatiana
• Senn, Joseph J.
• Lynn, Andy
• Bulychev, Alex
• McFadyen, Iain
• Chan, Joyce
• Almarsson, Örn
• Stanton, Matthew G.
• Benenato, Kerry E.

Titel

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

Ist Teil von

• Molecular therapy, 2018-06, Vol.26 (6), p.1509-1519

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. Sabnis et al. describe a novel amino lipid series for lipid nanoparticle-mediated delivery of mRNA. Enhanced delivery efficiency attributed to increased endosomal escape is demonstrated. An improved tolerability profile enables the first example of safe repeat dosing of mRNA containing lipid nanoparticles in non-human primate at therapeutically relevant levels.