Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Shiri Weinstein; Itai A. Toker; Rafi Emmanuel; Srinivas Ramishetti; Inbal Hazan-Halevy; Daniel Rosenblum; Meir Goldsmith; Avigdor Abraham; Ohad Benjamini; Osnat Bairey; Pia Raanani; Arnon Nagler; Judy Lieberman; Dan Peer

doi:10.1073/pnas.1519273113

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

Shiri Weinstein, Itai A. Toker, Rafi Emmanuel, Srinivas Ramishetti, Inbal Hazan-Halevy, Daniel Rosenblum, Meir Goldsmith, Avigdor Abraham, Ohad Benjamini, Osnat Bairey, Pia Raanani, Arnon Nagler, Judy Lieberman, Dan Peer

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

84 Scopus citations

Abstract

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.

Original language	English (US)
Pages (from-to)	E16-E22
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	1
DOIs	https://doi.org/10.1073/pnas.1519273113
State	Published - Jan 5 2016

Keywords

CD38
Cyclin D1
Mantle cell lymphoma
Nanomedicine
SiRNA

ASJC Scopus subject areas

General

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10.1073/pnas.1519273113

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Weinstein, S., Toker, I. A., Emmanuel, R., Ramishetti, S., Hazan-Halevy, I., Rosenblum, D., Goldsmith, M., Abraham, A., Benjamini, O., Bairey, O., Raanani, P., Nagler, A., Lieberman, J., & Peer, D. (2016). Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies. Proceedings of the National Academy of Sciences of the United States of America, 113(1), E16-E22. https://doi.org/10.1073/pnas.1519273113

Weinstein, S, Toker, IA, Emmanuel, R, Ramishetti, S, Hazan-Halevy, I, Rosenblum, D, Goldsmith, M, Abraham, A, Benjamini, O, Bairey, O, Raanani, P, Nagler, A, Lieberman, J & Peer, D 2016, 'Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 1, pp. E16-E22. https://doi.org/10.1073/pnas.1519273113

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abstract = "Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.",

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note = "Funding Information: We thank Dr. Leonid Mittelman and Dr. Vered Holdengreber for scientific assistance with confocal and electron microscopy and Andrew G. Sprague (Alnylam Pharmaceuticals) for providing siRNA and fluorescently labeled siRNA molecules. This work was supported in part by grants from the NIH (5R01CA139444-10); The Dotan Hematology Center at Tel Aviv University; The Lewis Family Trust; the Israel Science Foundation (Award #181/10); the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant 41/11) and the FTA: Nanomedicines for Personalized Theranostics of the Israeli National Nanotechnology Initiative; and by The Leona M. and Harry B. Helmsley Nanotechnology Research Fund (D.P.).",

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AU - Weinstein, Shiri

AU - Toker, Itai A.

AU - Emmanuel, Rafi

AU - Ramishetti, Srinivas

AU - Hazan-Halevy, Inbal

AU - Rosenblum, Daniel

AU - Goldsmith, Meir

AU - Abraham, Avigdor

AU - Benjamini, Ohad

AU - Bairey, Osnat

AU - Raanani, Pia

AU - Nagler, Arnon

AU - Lieberman, Judy

AU - Peer, Dan

N1 - Funding Information: We thank Dr. Leonid Mittelman and Dr. Vered Holdengreber for scientific assistance with confocal and electron microscopy and Andrew G. Sprague (Alnylam Pharmaceuticals) for providing siRNA and fluorescently labeled siRNA molecules. This work was supported in part by grants from the NIH (5R01CA139444-10); The Dotan Hematology Center at Tel Aviv University; The Lewis Family Trust; the Israel Science Foundation (Award #181/10); the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant 41/11) and the FTA: Nanomedicines for Personalized Theranostics of the Israeli National Nanotechnology Initiative; and by The Leona M. and Harry B. Helmsley Nanotechnology Research Fund (D.P.).

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N2 - Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Downregulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipidbased nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.

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Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies

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