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FORMULATION DEVELOPMENT OF siRNAs FOR DRUG DELIVERY: A NEW THERAPEUTIC APPROACH FOR PANDEMIC INFLUENZA.
Prieve, M.G., Ge, Q., Lamharzi, N., Cui, K., Thomson, A., Thompson, S., Templin, M., Wang, H., Farber, K., Roth, S., Houston, M., Johnson, P.H.
Nastech Pharmaceutical Company, Inc., Bothell, Washington.
Presented at the American Association of Pharmaceutical Sciences (AAPS) Biotechnology Conference, Boston, MA, June 18-21 (2006).
Keywords: Avian flu, Bird flu, Direct to lung administration, EpiAirway, Glycoprotiens, H5N1, Hemagluttin assay, Human bronchial epithelial tissue, Influenza viral replication, Intranasal delivery, Lipid formulation, Lung tissue, Mucus layer, Nucleotides, Pandemic influenza, SIRNAs, siRNAs
Endpoints: Cellular uptake of fluorescently labeled siRNA, Flu virus replication, Hemagluttin assay, MDCH-HA assay
Materials Tested: Cy5-siRNA, Lipis formulation siRNA, Peptide formulation siRNA
Summary:
The risk of an H5N1 Pandemic Flu outbreak is significant. New therapies to treat Influenza A viral infections are urgently needed.
Short interfering RNAs (siRNAs), targeting the conserved regions of influenza viral genes, have been shown to reduce viral replication in vitro and in vivo.
To provide an effective prophylactic and therapeutic treatment for pandemic flu, researchers at Nastech Pharmaceutical Co. are developing peptide and lipid formulations to efficiently deliver siRNAs to lung tissue. This involves studies on the biodistribution and cellular uptake of fluorescently labeled siRNA formulations in the mouse lung and evaluating their efficacy for knock-down of influenza viral replication.
Lipids were identified that facilitate siRNA uptake in vitro using EpiAirway primary human respiratory epithelial tissue.
Direct-to-lung administration of selected siRNAs reduced virus production in mice by 10-fold and with appropriate formulation by 200-fold.
Optimal, stable siRNA formulations for lung delivery will permit use of lower doses, reduced dosing frequency, and a longer duration of effect, thus providing a viable therapeutic approach to treat pandemic flu.
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