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

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• 作者：Thazha P. Prakash ; Walt F. Lima ; Heather M. Murray ; Sayda Elbashir ; William Cantley ; Don Foster ; Muthusamy Jayaraman ; Alfred E. Chappell ; Muthiah Manoharan ; Eric E. Swayze ; Stanley T. Crooke
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：July 19, 2013
• 年：2013
• 卷：8
• 期：7
• 页码：1402-1406
• 全文大小：488K
• 年卷期：v.8,no.7(July 19, 2013)
• ISSN：1554-8937

文摘

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鈥?(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.