title: Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.
abstract: Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic LNPs (cLNPs). The role of apoE was investigated using both in vitro studies employing recombinant apoE and in vivo studies in wild-type and apoE(-/-) mice. Receptor dependence was explored in vitro and in vivo using low-density lipoprotein receptor (LDLR(-/-))-deficient mice. As an alternative to endogenous apoE-based targeting, we developed a targeting approach using an exogenous ligand containing a multivalent N-acetylgalactosamine (GalNAc)-cluster, which binds with high affinity to the asialoglycoprotein receptor (ASGPR) expressed on hepatocytes. Both apoE-based endogenous and GalNAc-based exogenous targeting appear to be highly effective strategies for the delivery of iLNPs to liver.
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. aakinc@alnylam.com
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Soma
authors.initials: S
authors.lastname: De
authors.forename: June
authors.initials: J
authors.lastname: Qin
authors.forename: Maria
authors.initials: M
authors.lastname: Frank-Kamenetsky
authors.forename: K Narayanannair
authors.initials: KN
authors.lastname: Jayaprakash
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: William L
authors.initials: WL
authors.lastname: Cantley
authors.forename: J Robert
authors.initials: JR
authors.lastname: Dorkin
authors.forename: James S
authors.initials: JS
authors.lastname: Butler
authors.forename: Liuliang
authors.initials: L
authors.lastname: Qin
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.forename: Andrew
authors.initials: A
authors.lastname: Sprague
authors.forename: Eugenio
authors.initials: E
authors.lastname: Fava
authors.forename: Anja
authors.initials: A
authors.lastname: Zeigerer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope
authors.forename: Marino
authors.initials: M
authors.lastname: Zerial
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tracy
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Antonin de
authors.initials: Ad
authors.lastname: Fougerolles
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D037263:Asialoglycoprotein Receptor / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D034622:RNA Interference / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D037263:Asialoglycoprotein Receptor; D008024:Ligands; D011973:Receptors, LDL
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