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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1582-1589
Number of pages8
JournalMolecular Therapy
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Lip
Small Interfering RNA
Lipoproteins
Apolipoprotein E3
Apolipoprotein A-I
Cholesterol
RNA Interference
LDL Lipoproteins
Liver
HDL Lipoproteins
Messenger RNA
Therapeutics
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Nakayama, T., Butler, J. S., Sehgal, A., Severgnini, M., Racie, T., Sharman, J., ... 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
Nakayama, Tomoko ; Butler, James S. ; Sehgal, Alfica ; Severgnini, Mariano ; Racie, Tim ; Sharman, Jennifer ; Ding, Feng ; Morskaya, Svetlana Shulga ; Brodsky, Joshua ; Tchangov, Lubomir ; Kosovrasti, Verbena ; Meys, Mike ; Nechev, Lubomir ; Wang, Gang ; Peng, Chang Geng ; Fang, Yupang ; Maier, Martin ; Rajeev, Kallanthottathil G. ; Li, Robert ; Hettinger, Julia ; Barros, Scott ; Clausen, Valerie ; Zhang, Xuemei ; Wang, Qianfan ; Hutabarat, Renta ; Dokholyan, Nikolay V. ; Wolfrum, Christian ; Manoharan, Muthiah ; Kotelianski, Victor ; Stoffel, Markus ; Sah, Dinah W.Y. / Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles. In: Molecular Therapy. 2012 ; Vol. 20, No. 8. pp. 1582-1589.
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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

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

In: Molecular Therapy, Vol. 20, No. 8, 01.08.2012, p. 1582-1589.

Research output: Contribution to journalArticle

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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.

PY - 2012/8/1

Y1 - 2012/8/1

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Nakayama T, Butler JS, Sehgal A, Severgnini M, Racie T, Sharman J et al. Harnessing a physiologic mechanism for siRNA delivery with mimetic lipoprotein particles. Molecular Therapy. 2012 Aug 1;20(8):1582-1589. https://doi.org/10.1038/mt.2012.33