Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

Vignesh N. Hariharan; Minwook Shin; Ching Wen Chang; Daniel O’Reilly; Annabelle Biscans; Ken Yamada; Zhiru Guo; Mohan Somasundaran; Qi Tang; Kathryn Monopoli; Pranathi Meda Krishnamurthy; Gitali Devi; Nicholas McHugh; David A. Cooper; Dimas Echeverria; John Cruz; Io Long Chan; Ping Liu; Sun Young Lim; Jill McConnell; Satya Prakash Singh; Samuel Hildebrand; Jacquelyn Sousa; Sarah M. Davis; Zachary Kennedy; Chantal Ferguson; Bruno M.D.C. Godinho; Yann Thillier; Jillian Caiazzi; Socheata Ly; Manish Muhuri; Karen Kelly; Fiachra Humphries; Alyssa Cousineau; Krishna Mohan Parsi; Qi Li; Yang Wang; René Maehr; Guangping Gao; Dmitry Korkin; William M. McDougall; Robert W. Finberg; Katherine A. Fitzgerald; Jennifer P. Wang; Jonathan K. Watts; Anastasia Khvorova

doi:10.1073/pnas.2219523120

Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

Vignesh N. Hariharan, Minwook Shin, Ching Wen Chang, Daniel O’Reilly, Annabelle Biscans, Ken Yamada, Zhiru Guo, Mohan Somasundaran, Qi Tang, Kathryn Monopoli, Pranathi Meda Krishnamurthy, Gitali Devi, Nicholas McHugh, David A. Cooper, Dimas Echeverria, John Cruz, Io Long Chan, Ping Liu, Sun Young Lim, Jill McConnellSatya Prakash Singh, Samuel Hildebrand, Jacquelyn Sousa, Sarah M. Davis, Zachary Kennedy, Chantal Ferguson, Bruno M.D.C. Godinho, Yann Thillier, Jillian Caiazzi, Socheata Ly, Manish Muhuri, Karen Kelly, Fiachra Humphries, Alyssa Cousineau, Krishna Mohan Parsi, Qi Li, Yang Wang, René Maehr, Guangping Gao, Dmitry Korkin, William M. McDougall, Robert W. Finberg, Katherine A. Fitzgerald, Jennifer P. Wang, Jonathan K. Watts, Anastasia Khvorova

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

35 Scopus citations

Abstract

The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.

Original language	English (US)
Article number	e2219523120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	11
DOIs	https://doi.org/10.1073/pnas.2219523120
State	Published - Mar 10 2023
Externally published	Yes

Keywords

SARS-COV-2
antisense oligos
lung
mouse model
small interfering RNAs

ASJC Scopus subject areas

General

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10.1073/pnas.2219523120

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Hariharan, V. N., Shin, M., Chang, C. W., O’Reilly, D., Biscans, A., Yamada, K., Guo, Z., Somasundaran, M., Tang, Q., Monopoli, K., Krishnamurthy, P. M., Devi, G., McHugh, N., Cooper, D. A., Echeverria, D., Cruz, J., Chan, I. L., Liu, P., Lim, S. Y., ... Khvorova, A. (2023). Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection. Proceedings of the National Academy of Sciences of the United States of America, 120(11), Article e2219523120. https://doi.org/10.1073/pnas.2219523120

Hariharan, VN, Shin, M, Chang, CW, O’Reilly, D, Biscans, A, Yamada, K, Guo, Z, Somasundaran, M, Tang, Q, Monopoli, K, Krishnamurthy, PM, Devi, G, McHugh, N, Cooper, DA, Echeverria, D, Cruz, J, Chan, IL, Liu, P, Lim, SY, McConnell, J, Singh, SP, Hildebrand, S, Sousa, J, Davis, SM, Kennedy, Z, Ferguson, C, Godinho, BMDC, Thillier, Y, Caiazzi, J, Ly, S, Muhuri, M, Kelly, K, Humphries, F, Cousineau, A, Parsi, KM, Li, Q, Wang, Y, Maehr, R, Gao, G, Korkin, D, McDougall, WM, Finberg, RW, Fitzgerald, KA, Wang, JP, Watts, JK & Khvorova, A 2023, 'Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 11, e2219523120. https://doi.org/10.1073/pnas.2219523120

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title = "Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection",

abstract = "The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.",

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author = "Hariharan, {Vignesh N.} and Minwook Shin and Chang, {Ching Wen} and Daniel O{\textquoteright}Reilly and Annabelle Biscans and Ken Yamada and Zhiru Guo and Mohan Somasundaran and Qi Tang and Kathryn Monopoli and Krishnamurthy, {Pranathi Meda} and Gitali Devi and Nicholas McHugh and Cooper, {David A.} and Dimas Echeverria and John Cruz and Chan, {Io Long} and Ping Liu and Lim, {Sun Young} and Jill McConnell and Singh, {Satya Prakash} and Samuel Hildebrand and Jacquelyn Sousa and Davis, {Sarah M.} and Zachary Kennedy and Chantal Ferguson and Godinho, {Bruno M.D.C.} and Yann Thillier and Jillian Caiazzi and Socheata Ly and Manish Muhuri and Karen Kelly and Fiachra Humphries and Alyssa Cousineau and Parsi, {Krishna Mohan} and Qi Li and Yang Wang and Ren{\'e} Maehr and Guangping Gao and Dmitry Korkin and McDougall, {William M.} and Finberg, {Robert W.} and Fitzgerald, {Katherine A.} and Wang, {Jennifer P.} and Watts, {Jonathan K.} and Anastasia Khvorova",

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T1 - Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

AU - Hariharan, Vignesh N.

AU - Shin, Minwook

AU - Chang, Ching Wen

AU - O’Reilly, Daniel

AU - Biscans, Annabelle

AU - Yamada, Ken

AU - Guo, Zhiru

AU - Somasundaran, Mohan

AU - Tang, Qi

AU - Monopoli, Kathryn

AU - Krishnamurthy, Pranathi Meda

AU - Devi, Gitali

AU - McHugh, Nicholas

AU - Cooper, David A.

AU - Echeverria, Dimas

AU - Cruz, John

AU - Chan, Io Long

AU - Liu, Ping

AU - Lim, Sun Young

AU - McConnell, Jill

AU - Singh, Satya Prakash

AU - Hildebrand, Samuel

AU - Sousa, Jacquelyn

AU - Davis, Sarah M.

AU - Kennedy, Zachary

AU - Ferguson, Chantal

AU - Godinho, Bruno M.D.C.

AU - Thillier, Yann

AU - Caiazzi, Jillian

AU - Ly, Socheata

AU - Muhuri, Manish

AU - Kelly, Karen

AU - Humphries, Fiachra

AU - Cousineau, Alyssa

AU - Parsi, Krishna Mohan

AU - Li, Qi

AU - Wang, Yang

AU - Maehr, René

AU - Gao, Guangping

AU - Korkin, Dmitry

AU - McDougall, William M.

AU - Finberg, Robert W.

AU - Fitzgerald, Katherine A.

AU - Wang, Jennifer P.

AU - Watts, Jonathan K.

AU - Khvorova, Anastasia

PY - 2023/3/10

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N2 - The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.

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KW - mouse model

KW - small interfering RNAs

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JO - Proceedings of the National Academy of Sciences of the United States of America

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ER -

Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

Abstract

Keywords

ASJC Scopus subject areas

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