The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA
The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extra...
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Published in | Molecular therapy Vol. 24; no. 12; pp. 2100 - 2108 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier Inc
01.12.2016
Elsevier Limited Nature Publishing Group |
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Abstract | The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape. |
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AbstractList | The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro. Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape. The therapeutic applications of lipid nanoparticle (LNP) formulations of small interfering RNA (siRNA), are hampered by inefficient delivery of encapsulated siRNA to the cytoplasm following endocytosis. Recent work has shown that up to 70% of endocytosed LNP-siRNA particles are recycled to the extracellular medium and thus cannot contribute to gene silencing. Niemann-Pick type C1 (NPC1) is a late endosomal/lysosomal membrane protein required for efficient extracellular recycling of endosomal contents. Here we assess the influence of NP3.47, a putative small molecule inhibitor of NPC1, on the gene silencing potency of LNP-siRNA systems in vitro . Intracellular uptake and colocalization studies revealed that the presence of NP3.47 caused threefold or higher increases in accumulation of LNP-siRNA in late endosomes/lysosomes as compared with controls in a variety of cell lines. The gene silencing potency of LNP siRNA was enhanced up to fourfold in the presence of NP3.47. Mechanisms of action studies are consistent with the proposal that NP3.47 acts to inhibit NPC1. Our findings suggest that the pharmacological inhibition of NPC1 is an attractive strategy to enhance the therapeutic efficacy of LNP-siRNA by trapping LNP-siRNA in late endosomes, thereby increasing opportunities for endosomal escape. |
Author | Ciufolini, Marco A Chen, Sam van der Meel, Roy Wang, Haitang Zaifman, Josh Tam, Yuen Yi C Cullis, Pieter R |
Author_xml | – sequence: 1 givenname: Haitang surname: Wang fullname: Wang, Haitang organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada – sequence: 2 givenname: Yuen Yi C surname: Tam fullname: Tam, Yuen Yi C organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada – sequence: 3 givenname: Sam surname: Chen fullname: Chen, Sam organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada – sequence: 4 givenname: Josh surname: Zaifman fullname: Zaifman, Josh organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada – sequence: 5 givenname: Roy surname: van der Meel fullname: van der Meel, Roy organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada – sequence: 6 givenname: Marco A surname: Ciufolini fullname: Ciufolini, Marco A organization: Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada – sequence: 7 givenname: Pieter R surname: Cullis fullname: Cullis, Pieter R email: pieterc@mail.ubc.ca organization: Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada |
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SubjectTerms | Animals Biochemistry Carrier Proteins - antagonists & inhibitors Cell Line, Tumor Cholesterol Cytoplasm Drug Synergism Ebola virus Endosomes - chemistry Gene Silencing Health sciences HeLa Cells Humans Intracellular Signaling Peptides and Proteins Lipids Lipids - chemistry Localization Membrane Glycoproteins - antagonists & inhibitors Mice Molecular biology Nanoparticles Nanoparticles - chemistry Niemann-Pick C1 Protein NIH 3T3 Cells Original Proteins Proteins - antagonists & inhibitors RAW 264.7 Cells Recycling RNA, Small Interfering - pharmacology Small Molecule Libraries - pharmacology |
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Title | The Niemann-Pick C1 Inhibitor NP3.47 Enhances Gene Silencing Potency of Lipid Nanoparticles Containing siRNA |
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