Mechanistic modeling informed optimization of LNPs for mRNA drug delivery, efficacy, and dose prediction

抄録

Introduction: Lipid Nanoparticles (LNP) are novel vehicles for the delivery of Nucleic acid therapies (gene/mRNA/siRNA) and they have shown recent success in the development of COVID-19 mRNA vaccines. LNPs have multiple components:1) Ionizable lipid, 2) Helper lipid, 3) Cholesterol, and 4) PEG-lipid [1] and each plays a role in the observed ADME characteristics and final release of the cargo inside the cell. In addition, several features like the size, composition, pKa etc [2,3,4,5] also influence its distribution.

Objectives: The objective of this work is to identify the various aspects of LNPs that influence its Pharmacokinetic (PK) characteristics and incorporate these features into a mathematical model to support LNP optimization for novel therapies with focus on systemic delivery. By mapping the mRNA to protein synthesis, the model is used for dose-response prediction that subsequently informs dose optimization.

Methods: The proposed mechanistic model captures physical properties (such as size, composition, pKa etc) of LNPs and their impact on 1. Systemic distribution, 2. Cellular internalization, and 3. Intracellular cargo release. The model is calibrated to data from multiple preclinical studies and can be used to inform LNP optimization strategies for improved drug/cargo availability. Protein synthesis from mRNA is assumed to be a first order reaction and the produced protein expression is used as the surrogate marker for pharmacodynamic activity.

Results: The mechanistic model reported here can predict kinetics of LNPs based on their physical properties and chemical composition and hence can inform its optimization. Furthermore, by predicting the pharmacodynamics of delivered cargo, the model can inform dosing strategies.

Conclusions:The mechanistic modeling framework integrates diverse aspects of LNPs that can be engineered for optimizing systemic delivery of novel therapies.

References:

1. Hald Albertsen C et al, The role of lipid components in lipid nanoparticles for vaccines and gene therapy. doi: 10.1016/j.addr.2022.114416.

2. Chen S et al, Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA. doi: 10.1016/j.jconrel.2016.05.059

3. Nguyen TT et al, Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery. Pharmaceutics. doi: 10.3390/pharmaceutics14030572.

4. Radmand A et al, The Transcriptional Response to Lung-Targeting Lipid Nanoparticles in Vivo. doi: 10.1021/acs.nanolett.2c04479.

5. Jayaraman M et al, Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. doi: 10.1002/anie.201203263.