title: Lipid nanoparticles improve activity of single-stranded siRNA and gapmer antisense oligonucleotides in animals.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc. , 1896 Rutherford Road, Carlsbad, California 92008, United States.
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Walt F
authors.initials: WF
authors.lastname: Lima
authors.forename: Heather M
authors.initials: HM
authors.lastname: Murray
authors.forename: Sayda
authors.initials: S
authors.lastname: Elbashir
authors.forename: William
authors.initials: W
authors.lastname: Cantley
authors.forename: Don
authors.initials: D
authors.lastname: Foster
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chappell
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Crooke
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008055:Lipids; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase