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Review 1: "Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis"

This preprint analyzes the usage of RNAi molecules to create a potent prophylaxis against SARS-COV-2. Reviewers deemed this study strong and reliable with the only potential limitation being the lack of studies in different animal models.

Published onMay 19, 2022
Review 1: "Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis"
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key-enterThis Pub is a Review of
Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis

AbstractExpanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen with over 16,000 RNAi triggers against the SARS-CoV-2 genome using a massively parallel assay to identify hyper-potent siRNAs. We selected 10 candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity with IC50<20pM and strong neutralisation in live virus experiments. We further enhanced the activity by combinatorial pairing of the siRNA candidates to develop siRNA cocktails and found that these cocktails are active against multiple types of variants of concern (VOC). We examined over 2,000 possible mutations to the siRNA target sites using saturation mutagenesis and identified broad protection against future variants. Finally, we demonstrated that intranasal administration of the siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the Syrian hamster model. Our results pave the way to development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



The manuscript “Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis” by Ohad Yogev et al. described a novel RNAi-mediated strategy to prevent SRAS-CoV-2 infection in both in vitro tissue culture model and Syrian hamster model.

The study is of novelty and will enrich the current preventative tools in fighting against the SARS-CoV-2 pandemic. However, the experiment design is reasonable, and the paper is written in decent English.

Nevertheless, it could be improved by including the following contents:
1. The histology examination of nasal cavity and lung of SARS-CoV-2-infected hamsters treated with RNAi or not. In addition, the possible side effects of RNAi treatment should be discussed.
2. The authors are encouraged to include severe COVID-19 animal models, such as K18 mice, to evaluate the efficacy of RNAi treatments further. Meanwhile, the efficacy of RNAi on SARS-CoV-2 variants infection needs to be addressed in animal models as well.
3. Human lung epithelial cells culture system has been widely used in evaluating preventative or therapeutic options, and the authors are strongly encouraged to include this system in the revised version.
4. Finally, it will be interesting to determine the therapeutic efficacy of RNAi treatments by treating animals after infections. Or it needs to be discussed in the revised manuscript.


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