Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2

Jae Su Moon; Seung Hoon Lee; Song Hee Han; Eun Jung Kim; Hee Cho; Wooseong Lee; Mi Kyung Kim; Tae Eun Kim; Hyun Ji Park; Jin Kyu Rhee; Seong Jun Kim; Seung Woo Cho; Seung Hyun Han; Jong Won Oh

doi:10.1016/j.nano.2016.02.015

Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2

Jae Su Moon, Seung Hoon Lee, Song Hee Han, Eun Jung Kim, Hee Cho, Wooseong Lee, Mi Kyung Kim, Tae Eun Kim, Hyun Ji Park, Jin Kyu Rhee, Seong Jun Kim, Seung Woo Cho, Seung Hyun Han, Jong Won Oh

Department of Food Science & Biotechnology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Host-targeting antivirals have an advantage over direct-acting antivirals in that they have a high genetic barrier to resistance. Here, we describe in vivo anti-hepatitis C virus (HCV) efficacy of a potent siRNA targeting the protein kinase C-related kinase 2 (PRK2), which phosphorylates HCV NS5B RNA-dependent RNA polymerase and promotes HCV replication. PRK2-silencing reduced the phosphorylated NS5B level and resulted in inhibition of NS5B RdRp activity to decrease HCV genome abundance. Systemic administration of lipidoid nanoparticle-formulated PRK2 siRNA (once every three days for a total of three injections at a dose of 3 mg kg^-1) resulted in a 3.72 and 1.96 log₁₀ reduction in serum HCV RNA titer, in mouse subcutaneous and orthotopic xenograft models for HCV replication, respectively. Our results verify the essential role of PRK2 in HCV replication and offer a host-targeting anti-HCV siRNA therapy that might be beneficial for non-responders to current treatment regimens.

Original language	English
Pages (from-to)	1489-1498
Number of pages	10
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	12
Issue number	6
DOIs	https://doi.org/10.1016/j.nano.2016.02.015
State	Published - 1 Aug 2016

Bibliographical note

Funding Information:
Funding: This work was supported by a grant from the Technology Innovation Program (MKE 10035159) funded by the Ministry of Knowledge Economy (MKE, Korea) and in part by grants from the National Research Foundation of Korea funded by the Korea government (MSIP) (NRF 2009–0083522, 2010–0025982, 2013–063182, 2014R1A2A2A01005522, and COMPA 2014-11-1672).

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

Antivirals
HCV
Lipidoid
Nanoparticles
PRK2
SiRNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.nano.2016.02.015

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Moon, J. S., Lee, S. H., Han, S. H., Kim, E. J., Cho, H., Lee, W., Kim, M. K., Kim, T. E., Park, H. J., Rhee, J. K., Kim, S. J., Cho, S. W., Han, S. H., & Oh, J. W. (2016). Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2. Nanomedicine: Nanotechnology, Biology, and Medicine, 12(6), 1489-1498. https://doi.org/10.1016/j.nano.2016.02.015

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title = "Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2",

abstract = "Host-targeting antivirals have an advantage over direct-acting antivirals in that they have a high genetic barrier to resistance. Here, we describe in vivo anti-hepatitis C virus (HCV) efficacy of a potent siRNA targeting the protein kinase C-related kinase 2 (PRK2), which phosphorylates HCV NS5B RNA-dependent RNA polymerase and promotes HCV replication. PRK2-silencing reduced the phosphorylated NS5B level and resulted in inhibition of NS5B RdRp activity to decrease HCV genome abundance. Systemic administration of lipidoid nanoparticle-formulated PRK2 siRNA (once every three days for a total of three injections at a dose of 3 mg kg-1) resulted in a 3.72 and 1.96 log10 reduction in serum HCV RNA titer, in mouse subcutaneous and orthotopic xenograft models for HCV replication, respectively. Our results verify the essential role of PRK2 in HCV replication and offer a host-targeting anti-HCV siRNA therapy that might be beneficial for non-responders to current treatment regimens.",

keywords = "Antivirals, HCV, Lipidoid, Nanoparticles, PRK2, SiRNA",

author = "Moon, {Jae Su} and Lee, {Seung Hoon} and Han, {Song Hee} and Kim, {Eun Jung} and Hee Cho and Wooseong Lee and Kim, {Mi Kyung} and Kim, {Tae Eun} and Park, {Hyun Ji} and Rhee, {Jin Kyu} and Kim, {Seong Jun} and Cho, {Seung Woo} and Han, {Seung Hyun} and Oh, {Jong Won}",

note = "Funding Information: Funding: This work was supported by a grant from the Technology Innovation Program (MKE 10035159) funded by the Ministry of Knowledge Economy (MKE, Korea) and in part by grants from the National Research Foundation of Korea funded by the Korea government (MSIP) (NRF 2009–0083522, 2010–0025982, 2013–063182, 2014R1A2A2A01005522, and COMPA 2014-11-1672). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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Moon, JS, Lee, SH, Han, SH, Kim, EJ, Cho, H, Lee, W, Kim, MK, Kim, TE, Park, HJ, Rhee, JK, Kim, SJ, Cho, SW, Han, SH & Oh, JW 2016, 'Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2', Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 12, no. 6, pp. 1489-1498. https://doi.org/10.1016/j.nano.2016.02.015

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T1 - Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2

AU - Moon, Jae Su

AU - Lee, Seung Hoon

AU - Han, Song Hee

AU - Kim, Eun Jung

AU - Cho, Hee

AU - Lee, Wooseong

AU - Kim, Mi Kyung

AU - Kim, Tae Eun

AU - Park, Hyun Ji

AU - Rhee, Jin Kyu

AU - Kim, Seong Jun

AU - Cho, Seung Woo

AU - Han, Seung Hyun

AU - Oh, Jong Won

N1 - Funding Information: Funding: This work was supported by a grant from the Technology Innovation Program (MKE 10035159) funded by the Ministry of Knowledge Economy (MKE, Korea) and in part by grants from the National Research Foundation of Korea funded by the Korea government (MSIP) (NRF 2009–0083522, 2010–0025982, 2013–063182, 2014R1A2A2A01005522, and COMPA 2014-11-1672). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Host-targeting antivirals have an advantage over direct-acting antivirals in that they have a high genetic barrier to resistance. Here, we describe in vivo anti-hepatitis C virus (HCV) efficacy of a potent siRNA targeting the protein kinase C-related kinase 2 (PRK2), which phosphorylates HCV NS5B RNA-dependent RNA polymerase and promotes HCV replication. PRK2-silencing reduced the phosphorylated NS5B level and resulted in inhibition of NS5B RdRp activity to decrease HCV genome abundance. Systemic administration of lipidoid nanoparticle-formulated PRK2 siRNA (once every three days for a total of three injections at a dose of 3 mg kg-1) resulted in a 3.72 and 1.96 log10 reduction in serum HCV RNA titer, in mouse subcutaneous and orthotopic xenograft models for HCV replication, respectively. Our results verify the essential role of PRK2 in HCV replication and offer a host-targeting anti-HCV siRNA therapy that might be beneficial for non-responders to current treatment regimens.

AB - Host-targeting antivirals have an advantage over direct-acting antivirals in that they have a high genetic barrier to resistance. Here, we describe in vivo anti-hepatitis C virus (HCV) efficacy of a potent siRNA targeting the protein kinase C-related kinase 2 (PRK2), which phosphorylates HCV NS5B RNA-dependent RNA polymerase and promotes HCV replication. PRK2-silencing reduced the phosphorylated NS5B level and resulted in inhibition of NS5B RdRp activity to decrease HCV genome abundance. Systemic administration of lipidoid nanoparticle-formulated PRK2 siRNA (once every three days for a total of three injections at a dose of 3 mg kg-1) resulted in a 3.72 and 1.96 log10 reduction in serum HCV RNA titer, in mouse subcutaneous and orthotopic xenograft models for HCV replication, respectively. Our results verify the essential role of PRK2 in HCV replication and offer a host-targeting anti-HCV siRNA therapy that might be beneficial for non-responders to current treatment regimens.

KW - Antivirals

KW - HCV

KW - Lipidoid

KW - Nanoparticles

KW - PRK2

KW - SiRNA

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DO - 10.1016/j.nano.2016.02.015

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C2 - 27013134

AN - SCOPUS:84964994241

SN - 1549-9634

VL - 12

SP - 1489

EP - 1498

JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

IS - 6

ER -

Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2

Abstract

Bibliographical note

Keywords

UN SDGs

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