Lipid Nanoparticles Improve Activity of Single-Stranded siRNA and Gapmer Antisense Oligonucleotides in Animals

被引：41

作者：

Prakash, Thazha P. ^{[1
]}

Lima, Walt F. ^{[1
]}

Murray, Heather M. ^{[1
]}

Elbashir, Sayda ^{[2
]}

Cantley, William ^{[2
]}

Foster, Don ^{[2
]}

Jayaraman, Muthusamy ^{[2
]}

Chappell, Alfred E. ^{[1
]}

Manoharan, Muthiah ^{[2
]}

Swayze, Eric E. ^{[1
]}

Crooke, Stanley T. ^{[1
]}

机构：

[1] Isis Pharmaceut Inc, Dept Med Chem, Carlsbad, CA 92008 USA

[2] Alnylam Pharmaceut, Cambridge, MA 02142 USA

来源：

ACS CHEMICAL BIOLOGY | 2013年 / 8卷 / 07期

关键词：

SMALL INTERFERING RNA; IN-VIVO; MAMMALIAN-CELLS; CATIONIC LIPIDS; DELIVERY; THERAPEUTICS; TRANSFECTION; ARGONAUTE2; DUPLEXES; POTENCY;

D O I：

10.1021/cb4001316

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We evaluated the abilities of an antisense oligonucleotide (ASO), a small interfering RNA (siRNA), and a single-stranded siRNA (ss-siRNA) to inhibit expression from the PTEN gene in mice when formulated identically with lipid nanoparticles (LNPs). Significantly greater reductions in levels of PTEN mRNA were observed for LNP-formulated agents compared to unformulated drugs when gene silencing was evaluated after a single dose in the livers of mice. An unformulated ss-siRNA modified with a metabolically stable phosphate mimic 5'-(E)-vinylphosphonate showed dose-dependent reduction of PTEN mRNA in mice, albeit at doses significantly higher than those observed for formulated ss-siRNA. These results demonstrate that LNPs can be used to deliver functional antisense and ss-siRNA therapeutics to the liver, indicating that progress in the field of siRNA delivery is transferable to other classes of nucleic acid-based drugs.

引用

页码：1402 / 1406

页数：5

共 28 条

[1] Evaluation of Efficacy, Biodistribution, and Inflammation for a Potent siRNA Nanoparticle: Effect of Dexamethasone Co-treatment [J].

Abrams, Marc T. ;

Koser, Martin L. ;

Seitzer, Jessica ;

Williams, Stephanie C. ;

DiPietro, Martha A. ;

Wang, Weimin ;

Shaw, Andrew W. ;

Mao, Xianzhi ;

Jadhav, Vasant ;

Davide, Joseph P. ;

Burke, Paul A. ;

Sachs, Alan B. ;

Stirdivant, Steven M. ;

Sepp-Lorenzino, Laura .

MOLECULAR THERAPY, 2010, 18 (01) :171-180

[2] A combinatorial library of lipid-like materials for delivery of RNAi therapeutics [J].

Akinc, Akin ;

Zumbuehl, Andreas ;

Goldberg, Michael ;

Leshchiner, Elizaveta S. ;

Busini, Valentina ;

Hossain, Naushad ;

Bacallado, Sergio A. ;

Nguyen, David N. ;

Fuller, Jason ;

Alvarez, Rene ;

Borodovsky, Anna ;

Borland, Todd ;

Constien, Rainer ;

de Fougerolles, Antonin ;

Dorkin, J. Robert ;

Jayaprakash, K. Narayanannair ;

Jayaraman, Muthusamy ;

John, Matthias ;

Koteliansky, Victor ;

Manoharan, Muthiah ;

Nechev, Lubomir ;

Qin, June ;

Racie, Timothy ;

Raitcheva, Denitza ;

Rajeev, Kallanthottathil G. ;

Sah, Dinah W. Y. ;

Soutschek, Juergen ;

Toudjarska, Ivanka ;

Vornlocher, Hans-Peter ;

Zimmermann, Tracy S. ;

Langer, Robert ;

Anderson, Daniel G. .

NATURE BIOTECHNOLOGY, 2008, 26 (05) :561-569

[3] Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA [J].

Allerson, CR ;

Sioufi, N ;

Jarres, R ;

Prakash, TP ;

Naik, N ;

Berdeja, A ;

Wanders, L ;

Griffey, RH ;

Swayze, EE ;

Bhat, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (04) :901-904

[4]

Bakhtiyari S, 2013, THER DELIV, V4, P45, DOI [10.4155/tde.12.136, 10.4155/TDE.12.136]

[5] RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform [J].

Bennett, C. Frank ;

Swayze, Eric E. .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2010, 50 :259-293

[6] RNAi therapeutics: a potential new class of pharmaceutical drugs [J].

Bumcrot, David ;

Manoharan, Muthiah ;

Koteliansky, Victor ;

Sah, Dinah W. Y. .

NATURE CHEMICAL BIOLOGY, 2006, 2 (12) :711-719

[7]

Crooke StanleyT., 2008, Antisense Drug Technology: Principles, Strategies, and Applications

[8] Lipoplex-mediated delivery of nucleic acids: factors affecting in vivo transfection [J].

Dass, CR .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2004, 82 (09) :579-591

[9] Delivery vehicles for small interfering RNA in vivo [J].

De Fougerolles, Antonin R. .

HUMAN GENE THERAPY, 2008, 19 (02) :125-132

[10] Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells [J].

Elbashir, SM ;

Harborth, J ;

Lendeckel, W ;

Yalcin, A ;

Weber, K ;

Tuschl, T .

NATURE, 2001, 411 (6836) :494-498

← 1 2 3 →