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

Moschos, Sterghios A. and Frick, Manfred and Taylor, Bruce and Turnpenny, Paul and Graves, Helen and Spink, Karen G. and Brady, Kevin and Lambiel, David and Collins, David and Rockel, Thomas and Weber, Markus and Lazari, Ovadia and Perez-Tosar, Luis and Fancy, Sally A. and Lapthorn, Chris and Green, Martin X. and Evans, Steve and Selby, Matthew and Jones, Gareth and Jones, Lyn and Kearney, Sarah and Mechiche, Houria and Gikunju, Diana and Subramanian, Romesh and Uhlmann, Eugen and Jurk, Marion and Vollmer, Jörg and Ciaramella, Giuseppi and Yeadon, Michael (2011) Uptake, efficacy, and systemic distribution of naked, inhaled short interfering RNA (siRNA) and locked nucleic acid (LNA) antisense. Molecular Therapy, 19 (12). pp. 2163-2168. ISSN 1525-0016

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Official URL: http://dx.doi.org/10.1038/mt.2011.206

Abstract

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.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:10020
Deposited On:06 Oct 2011 14:32
Last Modified:16 Nov 2012 10:30

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