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Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system
Parhiz, Hamideh Shuvaev, Vladimir V. Li, Qin Papp, Tyler E. Akyianu, Awurama A. Shi, Ruiqi Yadegari, Amir Shahnawaz, Hamna Semple, Sean C. Mui, Barbara L.
Parhiz, Hamideh
Shuvaev, Vladimir V.
Li, Qin
Papp, Tyler E.
Akyianu, Awurama A.
Shi, Ruiqi
Yadegari, Amir
Shahnawaz, Hamna
Semple, Sean C.
Mui, Barbara L.
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Journal article
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2024-03-19
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Pharmaceutical Sciences
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https://doi.org/10.1016/j.omtn.2024.102175
Abstract
RNA therapeutics are an emerging, powerful class of drugs with potential applications in a wide range of disorders. A central challenge in their development is the lack of clear pharmacokinetic (PK)-pharmacodynamic relationship, in part due to the significant delay between the kinetics of RNA delivery and the onset of pharmacologic response. To bridge this gap, we have developed a physiologically based PK/pharmacodynamic model for systemically administered mRNA-containing lipid nanoparticles (LNPs) in mice. This model accounts for the physiologic determinants of mRNA delivery, active targeting in the vasculature, and differential transgene expression based on nanoparticle coating. The model was able to well-characterize the blood and tissue PKs of LNPs, as well as the kinetics of tissue luciferase expression measured by ex vivo activity in organ homogenates and bioluminescence imaging in intact organs. The predictive capabilities of the model were validated using a formulation targeted to intercellular adhesion molecule-1 and the model predicted nanoparticle delivery and luciferase expression within a 2-fold error for all organs. This modeling platform represents an initial strategy that can be expanded upon and utilized to predict the in vivo behavior of RNA-containing LNPs developed for an array of conditions and across species.
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Hamideh Parhiz, Vladimir V. Shuvaev, Qin Li, Tyler E. Papp, Awurama A. Akyianu, Ruiqi Shi, Amir Yadegari, Hamna Shahnawaz, Sean C. Semple, Barbara L. Mui, Drew Weissman, Vladimir R. Muzykantov, Patrick M. Glassman, Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system, Molecular Therapy - Nucleic Acids, Volume 35, Issue 2, 2024, 102175, ISSN 2162-2531, https://doi.org/10.1016/j.omtn.2024.102175. (https://www.sciencedirect.com/science/article/pii/S2162253124000623)
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Elsevier
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Molecular Therapy, Vol. 35, Iss. 2
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