A siRNA targets and inhibits a broad range of SARS‐CoV‐2 infections including Delta variant

The emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) variants has altered the trajectory of the COVID‐19 pandemic and raised some uncertainty on the long‐term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS‐CoV‐2 variants is i...

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Published in:	EMBO molecular medicine Vol. 14; no. 4; pp. e15298 - n/a
Main Authors:	Chang, Yi‐Chung, Yang, Chi‐Fan, Chen, Yi‐Fen, Yang, Chia‐Chun, Chou, Yuan‐Lin, Chou, Hung‐Wen, Chang, Tein‐Yao, Chao, Tai‐Ling, Hsu, Shu‐Chen, Ieong, Si‐Man, Tsai, Ya‐Min, Liu, Ping‐Cheng, Chin, Yuan‐Fan, Fang, Jun‐Tung, Kao, Han‐Chieh, Lu, Hsuan‐Ying, Chang, Jia‐Yu, Weng, Ren‐Shiuan, Tu, Qian‐Wen, Chang, Fang‐Yu, Huang, Kuo‐Yen, Lee, Tong‐Young, Chang, Sui‐Yuan, Yang, Pan‐Chyr
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 07-04-2022 EMBO Press John Wiley and Sons Inc Springer Nature
Subjects:	Aerosols Alveoli Animals Binding sites Candidates Coronaviruses COVID-19 Disease Models, Animal Disease transmission Drug development EMBO08 EMBO23 Gene expression Genomes Humans Infections inhalation K18‐hACE2‐transgenic mice Mice Mice, Transgenic Mutation Pandemics Proteins Respiratory syncytial virus RNA polymerase RNA, Small Interfering - genetics SARS-CoV-2 - genetics SARS‐CoV‐2 Severe acute respiratory syndrome coronavirus 2 siRNA Transgenic mice Vaccines Viral infections Virions Viruses inhalation siRNA COVID‐19 K18‐hACE2‐transgenic mice SARS‐CoV‐2 COVID-19 SARS-CoV-2 K18-hACE2-transgenic mice
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Summary:	The emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) variants has altered the trajectory of the COVID‐19 pandemic and raised some uncertainty on the long‐term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS‐CoV‐2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS‐CoV‐2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC 50 in vitro . Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18‐hACE2‐transgenic mice, accompanied by a significant prevention of virus‐associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggest that C6G25S provides an alternative and effective approach to combating the COVID‐19 pandemic. Synopsis C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration. A broadly active siRNA covers 99.8% of SARS‐CoV‐2 variants, including highly infective Delta and Omicron. C6G25S completely inhibited the Delta variant in lungs of infected mice by prophylactic treatment and decreased 93% of virions by co‐treatment. First study that use fully modified siRNA for inhalation and achieved promising therapeutic effect without a special delivery system. C6G25S is a safe, effective, and feasible therapeutic approach that could reach the market in a short time. Graphical Abstract C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration.
Bibliography:	et al April 2022 See also NAJ McMillan ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 See also: NAJ McMillan et al (April 2022)
ISSN:	1757-4676 1757-4684
DOI:	10.15252/emmm.202115298