Assessing siRNA pharmacodynamics in a luciferase-expressing mouse.
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.
Svensson
Robert U
RU
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.
Shey
Michael R
MR
Ballas
Zuhair K
ZK
Dorkin
J Robert
JR
Goldberg
Michael
M
Akinc
Akin
A
Langer
Robert
R
Anderson
Daniel G
DG
Bumcrot
David
D
Henry
Michael D
MD
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
D034741:RNA, Small Interfering; D008156:Luciferases
Nat Med. 2008 Jul;14(7):783-8
18542051
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5826-30
9159159
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6961-6
11997447
Photochem Photobiol. 1997 Oct;66(4):523-31
9337626
Nat Rev Drug Discov. 2008 Jul;7(7):591-607
18591980
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):221-6
14688412
Mol Imaging. 2004 Jan;3(1):63-8
15142413
Cancer Res. 2007 Aug 1;67(15):7525-33
17671224
Immunobiology. 2006;211(6-8):587-97
16920497
J Cell Biochem Suppl. 2002;39:239-48
12552623
Hum Gene Ther. 2007 Jul;18(7):575-88
17576157
Nature. 2007 Oct 11;449(7163):745-7
17898712
Neoplasia. 2000 Nov-Dec;2(6):491-5
11228541
Transplantation. 2005 Jul 15;80(1):134-9
16003245
Blood. 2003 Jan 15;101(2):640-8
12393519
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16551-5
12475931
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12044-9
10518573
Nat Rev Immunol. 2006 Jun;6(6):484-90
16724101
Mol Ther. 2001 Oct;4(4):297-306
11592831
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):489-94
11752392
Nat Biotechnol. 2008 May;26(5):561-9
18438401
Nature. 2006 May 4;441(7089):111-4
16565705
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
9108056
J Immunol. 2002 Feb 1;168(3):1441-6
11801687
Mol Imaging. 2003 Oct;2(4):297-302
14717328
Cancer Res. 2003 Nov 1;63(21):7042-6
14612492
Nat Rev Drug Discov. 2007 Jun;6(6):443-53
17541417
Nat Biotechnol. 2005 Jun;23(6):709-17
15908939
Nat Genet. 1999 Jan;21(1):70-1
9916792
Genes Dev. 1991 Sep;5(9):1513-23
1653172
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12177-82
16091473
Nat Biotechnol. 2006 Aug;24(8):1005-15
16823371
Mech Dev. 2001 Mar;101(1-2):61-9
11231059
Nat Methods. 2005 Aug;2(8):607-14
16094386
Cancer Res. 2007 Nov 1;67(21):10445-54
17974988