COVID-19 caused by the SARS-CoV-2 virus is a fast emerging disease with deadly consequences. The pulmonary system and lungs in particular are most prone to damage caused by the SARS-CoV-2 infection, which leaves a destructive footprint in the lung tissue, making it incapable of conducting its respiratory functions and resulting in severe acute respiratory disease and loss of life. There were no drug treatments or vaccines approved for SARS-CoV-2 at the onset of pandemic, necessitating an urgent need to develop effective therapeutics. To this end, the innate RNA interference (RNAi) mechanism can be employed to develop front line therapies against the virus. This approach allows specific binding and silencing of therapeutic targets by using short interfering RNA (siRNA) and short hairpin RNA (shRNA) molecules. In this review, we lay out the prospect of the RNAi technology for combatting the COVID-19. We first summarize current understanding of SARS-CoV-2 virology and the host response to viral entry and duplication, with the purpose of revealing effective RNAi targets. We then summarize the past experience with nucleic acid silencers for SARS-CoV, the predecessor for current SARS-CoV-2. Efforts targeting specific protein-coding regions within the viral genome and intragenomic targets are summarized. Emphasizing non-viral delivery approaches, molecular underpinnings of design of RNAi agents are summarized with comparative analysis of various systems used in the past. Promising viral targets as well as host factors are summarized, and the possibility of modulating the immune system are presented for more effective therapies. We place special emphasis on the limitations of past studies to propel the field faster by focusing on most relevant models to translate the promising agents to a clinical setting. Given the urgency to address lung failure in COVID-19, we summarize the feasibility of delivering promising therapies by the inhalational route, with the expectation that this route will provide the most effective intervention to halt viral spread. We conclude with the authors’ perspectives on the future of RNAi therapeutics for combatting SARS-CoV-2. Since time is of the essence, a strong perspective for the path to most effective therapeutic approaches are clearly articulated by the authors.

中文翻译：

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COVID-19 RNAi 治疗的前景

由 SARS-CoV-2 病毒引起的 COVID-19 是一种快速出现的疾病，具有致命的后果。肺系统，特别是肺部，最容易受到 SARS-CoV-2 感染造成的损害，这种感染会在肺组织中留下破坏性痕迹，使其无法执行呼吸功能，导致严重的急性呼吸道疾病和丧失生命力。生活。大流行爆发时，尚未批准针对 SARS-CoV-2 的药物治疗或疫苗，因此迫切需要开发有效的治疗方法。为此，先天RNA干扰（RNAi）机制可用于开发针对病毒的一线疗法。该方法通过使用短干扰 RNA (siRNA) 和短发夹 RNA (shRNA) 分子实现治疗靶点的特异性结合和沉默。在这篇综述中，我们阐述了 RNAi 技术对抗 COVID-19 的前景。我们首先总结了目前对 SARS-CoV-2 病毒学以及宿主对病毒进入和复制的反应的理解，目的是揭示有效的 RNAi 靶点。然后，我们总结了过去针对 SARS-CoV（当前 SARS-CoV-2 的前身）的核酸沉默剂的经验。总结了针对病毒基因组内特定蛋白质编码区域和基因组内目标的努力。强调非病毒递送方法，通过对过去使用的各种系统的比较分析，总结了 RNAi 制剂设计的分子基础。总结了有希望的病毒靶标和宿主因素，并提出了调节免疫系统以实现更有效治疗的可能性。我们特别强调过去研究的局限性，通过关注最相关的模型将有前途的药物转化为临床环境，从而更快地推动该领域的发展。鉴于解决 COVID-19 肺衰竭的紧迫性，我们总结了通过吸入途径提供有前景的治疗方法的可行性，并期望该途径将提供最有效的干预措施来阻止病毒传播。最后，我们总结了作者对对抗 SARS-CoV-2 的 RNAi 疗法的未来的看法。由于时间至关重要，作者清楚地阐述了最有效治疗方法的强烈观点。