Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense.

Sterghios Moschos, Manfred Frick, Bruce Taylor, Paul Turnpenny, Helen Graves, Karen Spink, Kevin Brady, David Lamb, David Collins, Thomas Rockel, Markus Weber, Ovadia Lazari, Luis Perez-Tosar, Sally-Ann Fancy, Chris Lapthorn, Martin Green, Steve Evans, Matthew Selby, Gareth Jones, Lyn JonesSarah Kearney, Houria Mechiche, Diana Gikunju, Romesh Subramanian, Eugen Uhlmann, Marion Jurk, Jörg Vollmer, Giuseppe Ciaramella, Michael Yeadon

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)


Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) promise specific correction of disease-causing gene expression. Therapeutic implementation, however, has been forestalled by poor delivery to the appropriate tissue, cell type, and subcellular compartment. Topical administration is considered to circumvent these issues. The availability of inhalation devices and unmet medical need in lung disease has focused efforts in this tissue. We report the development of a novel cell sorting method for quantitative, cell type-specific analysis of siRNA, and locked nucleic acid (LNA) ASO uptake and efficacy after intratracheal (i.t.) administration in mice. Through fluorescent dye labeling, we compare the utility of this approach to whole animal and whole tissue analysis, and examine the extent of tissue distribution. We detail rapid systemic access and renal clearance for both therapeutic classes and lack of efficacy at the protein level in lung macrophages, epithelia, or other cell types. We nevertheless observe efficient redirection of i.t. administered phosphorothioate (PS) LNA ASO to the liver and kidney leading to targeted gene knockdown. These data suggest delivery remains a key obstacle to topically administered, naked oligonucleotide efficacy in the lung and introduce inhalation as a potentially viable alternative to injection for antisense administration to the liver and kidneys.
Original languageEnglish
Pages (from-to)2163-2168
JournalMolecular Therapy
Issue number12
Early online date4 Oct 2011
Publication statusPublished - Dec 2011


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