Lipid nanoparticle delivery limits antisense oligonucleotide activity and cellular distribution in the brain after intracerebroventricular injection.

Autor:	Byrnes AE; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA., Dominguez SL; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA., Yen CW; Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA., Laufer BI; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.; Department of OMNI Bioinformatics, Genentech, Inc., South San Francisco, CA 94080, USA., Foreman O; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.; Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA., Reichelt M; Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA., Lin H; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA., Sagolla M; Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA., Hötzel K; Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA., Ngu H; Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA., Soendergaard C; Pharmaceutical Research and Early Development, Roche Innovation Center Copenhagen, Hørsholm, Denmark., Estevez A; Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080, USA., Lin HC; Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA., Goyon A; Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA., Bian J; Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA., Lin J; Synthetic Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, CA 94080, USA., Hinz FI; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA., Friedman BA; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.; Department of OMNI Bioinformatics, Genentech, Inc., South San Francisco, CA 94080, USA., Easton A; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA., Hoogenraad CC; Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 May 09; Vol. 32, pp. 773-793. Date of Electronic Publication: 2023 May 09 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.05.005
Abstrakt:	Antisense oligonucleotide (ASO) therapeutics are being investigated for a broad range of neurological diseases. While ASOs have been effective in the clinic, improving productive ASO internalization into target cells remains a key area of focus in the field. Here, we investigated how the delivery of ASO-loaded lipid nanoparticles (LNPs) affects ASO activity, subcellular trafficking, and distribution in the brain. We show that ASO-LNPs increase ASO activity up to 100-fold in cultured primary brain cells as compared to non-encapsulated ASO. However, in contrast to the widespread ASO uptake and activity observed following free ASO delivery in vivo , LNP-delivered ASOs did not downregulate mRNA levels throughout the brain after intracerebroventricular injection. This lack of activity was likely due to ASO accumulation in cells lining the ventricles and blood vessels. Furthermore, we reveal a formulation-dependent activation of the immune system post dosing, suggesting that LNP encapsulation cannot mask cellular ASO backbone-mediated toxicities. Together, these data provide insights into how LNP encapsulation affects ASO distribution as well as activity in the brain, and a foundation that enables future optimization of brain-targeting ASO-LNPs. Competing Interests: All authors are employees and shareholders of either F. Hoffmann-La Roche Ltd or Genentech, Inc., a member of the Roche group. (© 2023 The Authors.)
Databáze:	MEDLINE
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