Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles

Tomoko Nakayama; James S. Butler; Alfica Sehgal; Mariano Severgnini; Tim Racie; Jennifer Sharman; Feng Ding; Svetlana Shulga Morskaya; Joshua Brodsky; Lubomir Tchangov; Verbena Kosovrasti; Mike Meys; Lubomir Nechev; Gang Wang; Chang Geng Peng; Yupang Fang; Martin Maier; Kallanthottathil G. Rajeev; Robert Li; Julia Hettinger; Scott Barros; Valerie Clausen; Xuemei Zhang; Qianfan Wang; Renta Hutabarat; Nikolay V. Dokholyan; Christian Wolfrum; Muthiah Manoharan; Victor Kotelianski; Markus Stoffel; Dinah W.Y. Sah

doi:10.1038/mt.2012.33

Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles

Tomoko Nakayama, James S. Butler, Alfica Sehgal, Mariano Severgnini, Tim Racie, Jennifer Sharman, Feng Ding, Svetlana Shulga Morskaya, Joshua Brodsky, Lubomir Tchangov, Verbena Kosovrasti, Mike Meys, Lubomir Nechev, Gang Wang, Chang Geng Peng, Yupang Fang, Martin Maier, Kallanthottathil G. Rajeev, Robert Li, Julia HettingerScott Barros, Valerie Clausen, Xuemei Zhang, Qianfan Wang, Renta Hutabarat, Nikolay V. Dokholyan, Christian Wolfrum, Muthiah Manoharan, Victor Kotelianski, Markus Stoffel, Dinah W.Y. Sah

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Abstract

Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip-mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.

Original language	English (US)
Pages (from-to)	1582-1589
Number of pages	8
Journal	Molecular Therapy
Volume	20
Issue number	8
DOIs	https://doi.org/10.1038/mt.2012.33
State	Published - Aug 2012

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1038/mt.2012.33

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Nakayama, T., Butler, J. S., Sehgal, A., Severgnini, M., Racie, T., Sharman, J., Ding, F., Morskaya, S. S., Brodsky, J., Tchangov, L., Kosovrasti, V., Meys, M., Nechev, L., Wang, G., Peng, C. G., Fang, Y., Maier, M., Rajeev, K. G., Li, R., ... Sah, D. W. Y. (2012). Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles. Molecular Therapy, 20(8), 1582-1589. https://doi.org/10.1038/mt.2012.33

@article{4ac42c3f4cff4494bba9c9270378c692,

title = "Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles",

abstract = "Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip-mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.",

author = "Tomoko Nakayama and Butler, {James S.} and Alfica Sehgal and Mariano Severgnini and Tim Racie and Jennifer Sharman and Feng Ding and Morskaya, {Svetlana Shulga} and Joshua Brodsky and Lubomir Tchangov and Verbena Kosovrasti and Mike Meys and Lubomir Nechev and Gang Wang and Peng, {Chang Geng} and Yupang Fang and Martin Maier and Rajeev, {Kallanthottathil G.} and Robert Li and Julia Hettinger and Scott Barros and Valerie Clausen and Xuemei Zhang and Qianfan Wang and Renta Hutabarat and Dokholyan, {Nikolay V.} and Christian Wolfrum and Muthiah Manoharan and Victor Kotelianski and Markus Stoffel and Sah, {Dinah W.Y.}",

note = "Funding Information: We thank the following people at Alnylam Pharmaceuticals. John Maraganore for helpful discussions and critical reading of the manuscript; Maryellen Livingston and Lauren Lesser for graphics assistance; Akin Akinc for contribution to early A-lip work; Maria Frank-Kamenetsky, Yosef Landesman, Amy White, Jessica Sutherland, Kathy Mills, Amy Dell, Jeff Rollins, Mara Broberg, Christopher Zurenko, Bo Pang, Sergey Shulga-Morskoy, and David Butler for assistance and helpful suggestion. M.S. was supported by an SNF Sinergia grant and is a consultant and member of the Scientific Advisory Board of Alnylam Pharmaceuticals Inc..",

year = "2012",

month = aug,

doi = "10.1038/mt.2012.33",

language = "English (US)",

volume = "20",

pages = "1582--1589",

journal = "Molecular Therapy",

issn = "1525-0016",

publisher = "Nature Publishing Group",

number = "8",

}

Nakayama, T, Butler, JS, Sehgal, A, Severgnini, M, Racie, T, Sharman, J, Ding, F, Morskaya, SS, Brodsky, J, Tchangov, L, Kosovrasti, V, Meys, M, Nechev, L, Wang, G, Peng, CG, Fang, Y, Maier, M, Rajeev, KG, Li, R, Hettinger, J, Barros, S, Clausen, V, Zhang, X, Wang, Q, Hutabarat, R, Dokholyan, NV, Wolfrum, C, Manoharan, M, Kotelianski, V, Stoffel, M & Sah, DWY 2012, 'Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles', Molecular Therapy, vol. 20, no. 8, pp. 1582-1589. https://doi.org/10.1038/mt.2012.33

TY - JOUR

T1 - Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles

AU - Nakayama, Tomoko

AU - Butler, James S.

AU - Sehgal, Alfica

AU - Severgnini, Mariano

AU - Racie, Tim

AU - Sharman, Jennifer

AU - Ding, Feng

AU - Morskaya, Svetlana Shulga

AU - Brodsky, Joshua

AU - Tchangov, Lubomir

AU - Kosovrasti, Verbena

AU - Meys, Mike

AU - Nechev, Lubomir

AU - Wang, Gang

AU - Peng, Chang Geng

AU - Fang, Yupang

AU - Maier, Martin

AU - Rajeev, Kallanthottathil G.

AU - Li, Robert

AU - Hettinger, Julia

AU - Barros, Scott

AU - Clausen, Valerie

AU - Zhang, Xuemei

AU - Wang, Qianfan

AU - Hutabarat, Renta

AU - Dokholyan, Nikolay V.

AU - Wolfrum, Christian

AU - Manoharan, Muthiah

AU - Kotelianski, Victor

AU - Stoffel, Markus

AU - Sah, Dinah W.Y.

N1 - Funding Information: We thank the following people at Alnylam Pharmaceuticals. John Maraganore for helpful discussions and critical reading of the manuscript; Maryellen Livingston and Lauren Lesser for graphics assistance; Akin Akinc for contribution to early A-lip work; Maria Frank-Kamenetsky, Yosef Landesman, Amy White, Jessica Sutherland, Kathy Mills, Amy Dell, Jeff Rollins, Mara Broberg, Christopher Zurenko, Bo Pang, Sergey Shulga-Morskoy, and David Butler for assistance and helpful suggestion. M.S. was supported by an SNF Sinergia grant and is a consultant and member of the Scientific Advisory Board of Alnylam Pharmaceuticals Inc..

PY - 2012/8

Y1 - 2012/8

N2 - Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip-mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.

AB - Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip-mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.

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UR - http://www.scopus.com/inward/citedby.url?scp=84864544432&partnerID=8YFLogxK

U2 - 10.1038/mt.2012.33

DO - 10.1038/mt.2012.33

M3 - Article

C2 - 22850721

AN - SCOPUS:84864544432

SN - 1525-0016

VL - 20

SP - 1582

EP - 1589

JO - Molecular Therapy

JF - Molecular Therapy

IS - 8

ER -

Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles

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