title: Biodegradable lipid nanoparticles induce a prolonged RNA interference-mediated protein knockdown and show rapid hepatic clearance in mice and nonhuman primates.
abstract: Lipid nanoparticles based on ionizable lipids have been clinically validated as a means of delivery for RNA interference (RNAi) therapeutics. The ideal properties of RNAi carriers are efficient delivery of oligonucleotides into target cells and rapid elimination after the function is performed. Here, we report that degradable lipid nanoparticles are effective carriers of small interfering RNA (siRNA) and have a high therapeutic index. The newly developed degradable lipid nanoparticles carrying siRNA showed potent gene-silencing activity in mouse hepatocytes (ED50≈0.02mg/kg siRNA). The ester bond in the lipid tail was hydrolyzed in the liver, resulting in rapid metabolism of the lipid. Toxicity assays showed that the degradable lipid was well-tolerated at siRNA doses of up to 16mg/kg in rats (over 800-fold higher than ED50). A single intravenous injection of siRNA targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) in cynomolgus monkeys resulted in more than 90% protein silencing, and a 50% decrease in plasma low-density lipoprotein (LDL) cholesterol, with a measurable reduction for 2 months. Moreover, quantification of lipids in liver biopsies revealed rapid hepatic clearance of the degradable lipid in nonhuman primates. These degradable lipid nanoparticles with a high therapeutic index hold promise for RNA-based treatments.
authors.affiliation: DDS Research Group, Formulation Research Laboratories, Pharmaceutical Science and Technology, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: y14-suzuki@hhc.eisai.co.jp.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: DDS Research Group, Formulation Research Laboratories, Pharmaceutical Science and Technology, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: DDS Research Group, Formulation Research Laboratories, Pharmaceutical Science and Technology, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Fukuoka Development & Technical Group, Sogo Pharmaceuticals Co., Ltd., 408-1 Sonegasaki, Kamisokoino, Nakama, Fukuoka 809-0003, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: DDS Research Group, Formulation Research Laboratories, Pharmaceutical Science and Technology, Medicine Development Center, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D009841:Oligonucleotides / Q000378:metabolism; D011323:Primates; D000071449:Proprotein Convertase 9 / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008055:Lipids; D008077:Lipoproteins, LDL; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D002784:Cholesterol; D000071449:Proprotein Convertase 9
keywords: Biodegradable; Drug delivery; Gene silencing; Lipid nanoparticles; siRNA