2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Sherry Y. Wu; Xianbin Yang; Kshipra M. Gharpure; Hiroto Hatakeyama; Martin Egli; Michael H. McGuire; Archana S. Nagaraja; Takahito M. Miyake; Rajesha Rupaimoole; Chad V. Pecot; Morgan Taylor; Sunila Pradeep; Malgorzata Sierant; Cristian Rodriguez-Aguayo; Hyun J. Choi; Rebecca A. Previs; Guillermo N. Armaiz-Pena; Li Huang; Carlos Martinez; Tom Hassell; Cristina Ivan; Vasudha Sehgal; Richa Singhania; Hee Dong Han; Chang Su; Ji Hoon Kim; Heather J. Dalton; Chandra Kovvali; Khandan Keyomarsi; Nigel A.J. McMillan; Willem W. Overwijk; Jinsong Liu; Ju Seog Lee; Keith A. Baggerly; Gabriel Lopez-Berestein; Prahlad T. Ram; Barbara Nawrot; Anil K. Sood

doi:10.1038/ncomms4459

2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Sherry Y. Wu, Xianbin Yang, Kshipra M. Gharpure, Hiroto Hatakeyama, Martin Egli, Michael H. McGuire, Archana S. Nagaraja, Takahito M. Miyake, Rajesha Rupaimoole, Chad V. Pecot, Morgan Taylor, Sunila Pradeep, Malgorzata Sierant, Cristian Rodriguez-Aguayo, Hyun J. Choi, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Li Huang, Carlos Martinez, Tom HassellCristina Ivan, Vasudha Sehgal, Richa Singhania, Hee Dong Han, Chang Su, Ji Hoon Kim, Heather J. Dalton, Chandra Kovvali, Khandan Keyomarsi, Nigel A.J. McMillan, Willem W. Overwijk, Jinsong Liu, Ju Seog Lee, Keith A. Baggerly, Gabriel Lopez-Berestein, Prahlad T. Ram, Barbara Nawrot, Anil K. Sood

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

118 Citations (Scopus)

Abstract

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

Original language	English
Article number	3459
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4459
Publication status	Published - 2014 Mar 12
Externally published	Yes

Bibliographical note

Funding Information:
S.Y.W. is supported by Ovarian Cancer Research Fund, Foundation for Women’s Cancer, and Cancer Prevention Research Institute of Texas training grants (RP101502, RP101489 and RP110595). Portions of this work were supported by the NIH (GM100777-01, GM086937-01, GM084552-04, CA016672, CA109298, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, UH2 TR000943-01 and U24CA143835), NCI-DHHS-NIH T32 Training grant (T32 CA101642), the DOD (OC120547 and OC093416), the Ovarian Cancer Research Fund (Programme Project Development Grant), the Blanton-Davis Ovarian Cancer Research Program, the RGK Foundation, the Gilder Foundation, the Betty Anne Asche Murray Distinguished Professorship and statutory funds of the Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences. We thank D. Ruder, D. Reynolds, J. Seymour, S. Dorta-Estremera, N. Sadaoui, Drs. M. Ravoori, R. Langley, X.F. Huang, C.H. Lu, J. Filant, W. Cao and members of the histology, flow cytometry and siRNA screening facilities at the University of Texas MD Anderson Cancer Center for technical assistance, provision of study materials and/or helpful suggestions on the manuscript.

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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

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10.1038/ncomms4459

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Wu, S. Y., Yang, X., Gharpure, K. M., Hatakeyama, H., Egli, M., McGuire, M. H., Nagaraja, A. S., Miyake, T. M., Rupaimoole, R., Pecot, C. V., Taylor, M., Pradeep, S., Sierant, M., Rodriguez-Aguayo, C., Choi, H. J., Previs, R. A., Armaiz-Pena, G. N., Huang, L., Martinez, C., ... Sood, A. K. (2014). 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nature communications, 5, Article 3459. https://doi.org/10.1038/ncomms4459

Wu, SY, Yang, X, Gharpure, KM, Hatakeyama, H, Egli, M, McGuire, MH, Nagaraja, AS, Miyake, TM, Rupaimoole, R, Pecot, CV, Taylor, M, Pradeep, S, Sierant, M, Rodriguez-Aguayo, C, Choi, HJ, Previs, RA, Armaiz-Pena, GN, Huang, L, Martinez, C, Hassell, T, Ivan, C, Sehgal, V, Singhania, R, Han, HD, Su, C, Kim, JH, Dalton, HJ, Kovvali, C, Keyomarsi, K, McMillan, NAJ, Overwijk, WW, Liu, J, Lee, JS, Baggerly, KA, Lopez-Berestein, G, Ram, PT, Nawrot, B & Sood, AK 2014, '2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity', Nature communications, vol. 5, 3459. https://doi.org/10.1038/ncomms4459

@article{bb8c07e9907448888d1da7c6db733d6a,

title = "2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity",

abstract = "Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.",

author = "Wu, {Sherry Y.} and Xianbin Yang and Gharpure, {Kshipra M.} and Hiroto Hatakeyama and Martin Egli and McGuire, {Michael H.} and Nagaraja, {Archana S.} and Miyake, {Takahito M.} and Rajesha Rupaimoole and Pecot, {Chad V.} and Morgan Taylor and Sunila Pradeep and Malgorzata Sierant and Cristian Rodriguez-Aguayo and Choi, {Hyun J.} and Previs, {Rebecca A.} and Armaiz-Pena, {Guillermo N.} and Li Huang and Carlos Martinez and Tom Hassell and Cristina Ivan and Vasudha Sehgal and Richa Singhania and Han, {Hee Dong} and Chang Su and Kim, {Ji Hoon} and Dalton, {Heather J.} and Chandra Kovvali and Khandan Keyomarsi and McMillan, {Nigel A.J.} and Overwijk, {Willem W.} and Jinsong Liu and Lee, {Ju Seog} and Baggerly, {Keith A.} and Gabriel Lopez-Berestein and Ram, {Prahlad T.} and Barbara Nawrot and Sood, {Anil K.}",

note = "Funding Information: S.Y.W. is supported by Ovarian Cancer Research Fund, Foundation for Women{\textquoteright}s Cancer, and Cancer Prevention Research Institute of Texas training grants (RP101502, RP101489 and RP110595). Portions of this work were supported by the NIH (GM100777-01, GM086937-01, GM084552-04, CA016672, CA109298, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, UH2 TR000943-01 and U24CA143835), NCI-DHHS-NIH T32 Training grant (T32 CA101642), the DOD (OC120547 and OC093416), the Ovarian Cancer Research Fund (Programme Project Development Grant), the Blanton-Davis Ovarian Cancer Research Program, the RGK Foundation, the Gilder Foundation, the Betty Anne Asche Murray Distinguished Professorship and statutory funds of the Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences. We thank D. Ruder, D. Reynolds, J. Seymour, S. Dorta-Estremera, N. Sadaoui, Drs. M. Ravoori, R. Langley, X.F. Huang, C.H. Lu, J. Filant, W. Cao and members of the histology, flow cytometry and siRNA screening facilities at the University of Texas MD Anderson Cancer Center for technical assistance, provision of study materials and/or helpful suggestions on the manuscript.",

year = "2014",

month = mar,

day = "12",

doi = "10.1038/ncomms4459",

language = "English",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

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TY - JOUR

T1 - 2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

AU - Wu, Sherry Y.

AU - Yang, Xianbin

AU - Gharpure, Kshipra M.

AU - Hatakeyama, Hiroto

AU - Egli, Martin

AU - McGuire, Michael H.

AU - Nagaraja, Archana S.

AU - Miyake, Takahito M.

AU - Rupaimoole, Rajesha

AU - Pecot, Chad V.

AU - Taylor, Morgan

AU - Pradeep, Sunila

AU - Sierant, Malgorzata

AU - Rodriguez-Aguayo, Cristian

AU - Choi, Hyun J.

AU - Previs, Rebecca A.

AU - Armaiz-Pena, Guillermo N.

AU - Huang, Li

AU - Martinez, Carlos

AU - Hassell, Tom

AU - Ivan, Cristina

AU - Sehgal, Vasudha

AU - Singhania, Richa

AU - Han, Hee Dong

AU - Su, Chang

AU - Kim, Ji Hoon

AU - Dalton, Heather J.

AU - Kovvali, Chandra

AU - Keyomarsi, Khandan

AU - McMillan, Nigel A.J.

AU - Overwijk, Willem W.

AU - Liu, Jinsong

AU - Lee, Ju Seog

AU - Baggerly, Keith A.

AU - Lopez-Berestein, Gabriel

AU - Ram, Prahlad T.

AU - Nawrot, Barbara

AU - Sood, Anil K.

N1 - Funding Information: S.Y.W. is supported by Ovarian Cancer Research Fund, Foundation for Women’s Cancer, and Cancer Prevention Research Institute of Texas training grants (RP101502, RP101489 and RP110595). Portions of this work were supported by the NIH (GM100777-01, GM086937-01, GM084552-04, CA016672, CA109298, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, UH2 TR000943-01 and U24CA143835), NCI-DHHS-NIH T32 Training grant (T32 CA101642), the DOD (OC120547 and OC093416), the Ovarian Cancer Research Fund (Programme Project Development Grant), the Blanton-Davis Ovarian Cancer Research Program, the RGK Foundation, the Gilder Foundation, the Betty Anne Asche Murray Distinguished Professorship and statutory funds of the Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences. We thank D. Ruder, D. Reynolds, J. Seymour, S. Dorta-Estremera, N. Sadaoui, Drs. M. Ravoori, R. Langley, X.F. Huang, C.H. Lu, J. Filant, W. Cao and members of the histology, flow cytometry and siRNA screening facilities at the University of Texas MD Anderson Cancer Center for technical assistance, provision of study materials and/or helpful suggestions on the manuscript.

PY - 2014/3/12

Y1 - 2014/3/12

N2 - Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

AB - Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

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U2 - 10.1038/ncomms4459

DO - 10.1038/ncomms4459

M3 - Article

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AN - SCOPUS:84896259886

SN - 2041-1723

VL - 5

JO - Nature communications

JF - Nature communications

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ER -

2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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