title: Assessing siRNA pharmacodynamics in a luciferase-expressing mouse.
abstract: A significant barrier to the successful general development of small-interfering RNA (siRNA) therapeutics is the ability to deliver them systemically to target organs and cell types. In this study, we have developed a mouse strain that will facilitate the evaluation of the efficacy of siRNA delivery strategies. This strain contains robust ubiquitous expression of firefly luciferase from germ line Cre-mediated recombination of the ROSA26-LSL-Luc allele. We show that luciferase is highly and uniformly expressed in all tissues examined. Using this mouse model, we describe a facile assay that enables the assessment of the pharmacodynamics of a systemically delivered siRNA formulation. These mice can also be used as universal donors, enabling the efficient and sensitive monitoring of cell trafficking or tissue transplantation. The primary advantage of this approach is that siRNA efficacy against a nonessential target can be easily evaluated in any tissue. This strain should generally enhance the ability to rapidly screen, compare and optimize various siRNA formulations for tissue-targeted or -enhanced systemic delivery in a preclinical development setting.
authors.affiliation: Department of Molecular Physiology and Biophysics and Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52240, USA.
authors.forename: Robert U
authors.initials: RU
authors.lastname: Svensson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Shey
authors.forename: Zuhair K
authors.initials: ZK
authors.lastname: Ballas
authors.forename: J Robert
authors.initials: JR
authors.lastname: Dorkin
authors.forename: Michael
authors.initials: M
authors.lastname: Goldberg
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.forename: David
authors.initials: D
authors.lastname: Bumcrot
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008156:Luciferases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000032:analysis / Q000235:genetics* / Q000493:pharmacokinetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D034741:RNA, Small Interfering; D008156:Luciferases
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