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

Abstract

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.

mRNA as novel technology for passive immunotherapy

“…For Pardi et al the observation that modified nucleotides can hamper the function of IRES elements may have affected the selection [218]. Sabnis et al also worked with a full IgG antibody, directed against influenza A, but did not provide any details on how heavy and light chain were represented [269]. In contrast, Stadler et al chose BiTE antibodies directed against TCR-associated CD3 and one of three different tumor-associated antigens (TAAs) [264].…”

“…While previous in vivo studies on mRNA-mediated antibody expression were limited to mice, Sabnis et al presented expression results in NHPs using a proprietary LNP formulation [269]. A 0.3 mg/kg dose of mRNA gave rise to antibody serum titers of about 4 µg/ml 24 h after IV administration which is at least at the lower end of the range of efficacy observed in mouse studies.…”

Messenger RNA therapy for rare genetic metabolic diseases

“…A critical factor that will determine the success of the mRNA-based therapy will be the lack of toxicity due to accumulation of the LNPs, as slight differences in the tolerability of LNPs may dramatically influence the long-term safety 62. Active research in this area is leading to the development of innovative LNPs with very good pharmacokinetics and importantly with a favourable toxicity profile tested in non-human primates after repeated administrations 16. A comparative analysis of protein replacement therapy, gene therapy and mRNA-based therapy is presented in table 1.…”

“…Once in the endosome, the ionisable lipids induce the endosome escape of the LNP with the mRNA cargo, which will be finally released into the cytoplasm 16 17. Optimisation of all LNP components has led to the development of LNPs that mediate robust transduction of modified mRNA into non-human primate hepatocytes 16. These LNPs are characterised by high delivery rates, better endosomal escape once invaginated to the cell and high rate of biodegradability resulting in low accumulation of lipids in the targeted organs 16.…”

“…Optimisation of all LNP components has led to the development of LNPs that mediate robust transduction of modified mRNA into non-human primate hepatocytes 16. These LNPs are characterised by high delivery rates, better endosomal escape once invaginated to the cell and high rate of biodegradability resulting in low accumulation of lipids in the targeted organs 16. Such features are important for rare genetic disorders where safety is paramount for young patients affected by these diseases.…”