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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: Publikationen MPI-CBG 2010-arch     Display Documents



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ID: 546657.0, MPI für molekulare Zellbiologie und Genetik / Publikationen MPI-CBG 2010-arch
Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms.
Authors:Akinc, Akin; Querbes, William; De, Soma; Qin, June; Frank-Kamenetsky, Maria; Jayaprakash, K Narayanannair; Jayaraman, Muthusamy; Rajeev, Kallanthottathil G; Cantley, William L; Dorkin, J Robert; Butler, James S; Qin, Liuliang; Racie, Timothy; Sprague, Andrew; Fava, Eugenio; Zeigerer, Anja; Hope, Michael J; Zerial, Marino; Sah, Dinah W Y; Fitzgerald, Kevin; Tracy, Mark A; Manoharan, Muthiah; Koteliansky, Victor; Fougerolles, Antonin de; Maier, Martin A
Date of Publication (YYYY-MM-DD):2010
Title of Journal:Molecular Therapy : the Journal of the American Society of Gene Therapy
Volume:18
Issue / Number:7
Start Page:1357
End Page:1364
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:nn
Affiliations:MPI für molekulare Zellbiologie und Genetik
Identifiers:LOCALID:4234
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