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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 11 Pg. e2219523120 (03 14 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 36893269 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• RNA, Small Interfering
• Antiviral Agents
• Oligonucleotides

Topics

• Humans
• Animals
• Mice
• RNA, Small Interfering (genetics)
• COVID-19 (therapy)
• SARS-CoV-2 (genetics)
• Antiviral Agents (pharmacology, therapeutic use)
• Oligonucleotides
• Lung