Nature Chemical Biology ( IF 14.8 ) Pub Date : 2022-07-25 , DOI: 10.1038/s41589-022-01094-4 Zhifen Cui 1 , Cong Zeng 2 , Furong Huang 1 , Fuwen Yuan 1 , Jingyue Yan 3 , Yue Zhao 1, 4 , Yufan Zhou 5 , William Hankey 1 , Victor X Jin 5 , Jiaoti Huang 1 , Herman F Staats 1, 6 , Jeffrey I Everitt 1 , Gregory D Sempowski 1, 6 , Hongyan Wang 1 , Yizhou Dong 3 , Shan-Lu Liu 2 , Qianben Wang 1
SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR–Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection.
中文翻译:
Cas13d 敲低肺蛋白酶 Ctsl 可预防和治疗 SARS-CoV-2 感染
SARS-CoV-2 进入细胞需要特定的宿主蛋白酶;然而,尚未报道宿主蛋白酶抑制剂在体内成功用于治疗 SARS-CoV-2 发病机制。在这里,我们描述了一种封装 CRISPR-Cas13d 的化学工程纳米系统,该系统专门针对肺蛋白酶组织蛋白酶 L ( Ctsl ) 信使 RNA 开发,以阻断小鼠的 SARS-CoV-2 感染。我们表明该纳米系统可降低肺Ctsl在正常小鼠中高效、特异、安全地表达。我们进一步表明,这种方法延长了感染 SARS-CoV-2 的小鼠的存活期,与肺病毒负荷降低、促炎细胞因子/趋化因子表达降低以及肺间质炎症严重程度降低相关。这种纳米系统的感染后治疗可显着降低肺部病毒负荷并减轻病毒引起的病理变化。我们的结果表明,Cas13d 纳米系统靶向肺蛋白酶 mRNA 代表了控制 SARS-CoV-2 感染的独特策略,并证明 CRISPR 可用作 SARS-CoV-2 感染的潜在治疗方法。