1. Lung-selective Cas13d-based nanotherapy inhibits lethal SARS-CoV-2 infection by targeting host protease Ctsl
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Yue Zhao, Herman F. Staats, Jeffrey I. Everitt, Yizhou Dong, Jiaoti Huang, Cui Zhifen, Furong Huang, Cong Zeng, Qianben Wang, Jingyue Yan, Fuwen Yuan, Shan-Lu Liu, Gregory D. Sempowski, and Hongyan Wang more...
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Gene knockdown ,Chemokine ,Proteases ,biology ,business.industry ,TMPRSS2 ,Virus ,respiratory tract diseases ,Pathogenesis ,Cathepsin L ,In vivo ,Cancer research ,biology.protein ,Medicine ,business - Abstract
SUMMARYThe COVID-19 pandemic persists as a global health crisis for which curative treatment has been elusive. Development of effective and safe anti-SARS-CoV-2 therapies remains an urgent need. SARS-CoV-2 entry into cells requires specific host proteases including TMPRSS2 and Cathepsin L (Ctsl)1–3, but there has been no reported success in inhibiting host proteases for treatment of SARS-CoV-2 pathogenesis in vivo. Here we have developed a lung Ctsl mRNA-targeted, CRISPR/Cas13d-based nanoparticle therapy to curb fatal SARS-CoV-2 infection in a mouse model. We show that this nanotherapy can decrease lung Ctsl expression in normal mice efficiently, specifically, and safely. Importantly, this lung-selective Ctsl-targeted nanotherapy significantly extended the survival of lethally SARS-CoV-2 infected mice by decreasing lung virus burden, reducing expression of pro-inflammatory cytokines/chemokines, and diminishing the severity of pulmonary interstitial inflammation. Additional in vitro analyses demonstrated that Cas13d-mediated Ctsl knockdown inhibited infection mediated by the spike protein of SARS-CoV-1, SARS-CoV-2, and more importantly, the authentic SARS-CoV-2 B.1.617.2 Delta variant, regardless of TMPRSS2 expression status. Our results demonstrate the efficacy and safety of a lung-selective, Ctsl-targeted nanotherapy against infection by SARS-CoV-2 and likely other emerging coronaviruses, forming a basis for investigation of this approach in clinical trials. more...
- Published
- 2021
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