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International Journal of Pharmacokinetics
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Therapeutic Delivery
Bioanalytical Challenge

Overcoming analytical challenges to generate data critical to understanding lipid nanoparticle-delivered modified mRNA biodistribution

    Glen Hawthorne

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK

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    ,
    Neil Henderson

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

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    ,
    Mikko Hölttä

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

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    ,
    Sima Khan

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK

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    ,
    Johnny Lindqvist

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

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    &
    Amanda Wilson

    *Author for correspondence:

    E-mail Address: Amanda.Wilson@astrazeneca.com

    Translational Biomarkers and Bioanalysis, Clinical Pharmacology Biologics & Bioanalysis, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK

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    Published Online:16 Oct 2019https://doi.org/10.4155/bio-2019-0138

    Abstract

    Aim: Chemically modified mRNA offers a novel approach to treat disease. Due to susceptibility to extracellular nucleases in vivo, dosed modified mRNA therapeutics can benefit from encapsulation within novel delivery systems, such as lipid nanoparticles (LNPs). To understand the holistic effect of dosing LNP-encapsulated modified mRNA therapeutics can require bioanalysis of several components including the mRNA, protein and LNP. Methodology: These components can require bespoke preanalytical strategies to preserve analyte integrity to achieve successful analysis. Here we describe the sample collection, processing steps and bioanalytical technologies that can be used to overcome these challenges. Discussion: Understanding the biodistribution and holistic effects of the different components allow the pharmaceutical industry to evaluate safety and efficacy of modified mRNA therapeutics.

    References

    • 1. Sahin U, Kariko K, Tureci O. mRNA-based therapeutics – developing a new class of drugs. Nat. Rev. Drug Discov. 13(10), 759–780 (2014).
      Medline CASGoogle Scholar
    • 2. Kowalski PS, Rudra A, Miao L, Anderson DG. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27(4), 710–728 (2019).
      Medline CASGoogle Scholar
    • 3. Sedic M, Senn JJ, Lynn A et al. Safety evaluation of lipid nanoparticle-formulated modified mRNA in the Sprague–Dawley rat and cynomolgus monkey. Vet. Pathol. 55(2), 341–354 (2018).
      Medline CASGoogle Scholar
    • 4. Robinson E, MacDonald KD, Slaughter K et al. Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Mol. Ther. 26(8), 2034–2046 (2018).
      Medline CASGoogle Scholar
    • 5. Morgan P, Brown DG, Lennard S et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat. Rev. Drug. Discov. 17(3), 167–181 (2018).
      Medline CASGoogle Scholar
    • 6. Bayatti N, Cooper-Knock J, Bury JJ et al. Comparison of blood RNA extraction methods used for gene expression profiling in amyotrophic lateral sclerosis. PLoS ONE 9(1), e87508 (2014).
      MedlineGoogle Scholar
    • 7. Seitzer J, Zhang H, Koser M, Pei Y, Abrams M. Effect of biological matrix and sample preparation on qPCR quantitation of siRNA drugs in animal tissues. J. Pharmacol. Toxicol. Methods 63(2), 16873 (2011).
      Google Scholar
    • 8. Zangi L, Lui KO, von Gise A et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 31(10), 898907 (2013).
      Google Scholar
    • 9. Gan LM, Lagerstrom-Fermer M, Carlsson LG et al. Intradermal delivery of modified mRNA encoding VEGF-A in patients with Type 2 diabetes. Nat. Commun. 10(1), 871 (2019).
      MedlineGoogle Scholar
    • 10. Hawthorne G, Harbach S, Wilson A. Cationic lipid bioanalysis: understanding distribution of lipid nanoparticles for delivery of RNA therapeutics. Bioanalysis 10(5), 275–277 (2018).
      CASGoogle Scholar
    • 11. Pehrsson S, Holtta M, Linhardt G, Danielson RF, Carlsson L. Rapid production of human VEGF-A following intradermal injection of modified VEGF-A mRNA demonstrated by cutaneous microdialysis in the rabbit and pig in vivo. BioMed Res. Int. 2019, 3915851 (2019).
      MedlineGoogle Scholar