mRNA-encoded Cas13 as a pan-respiratory antiviral

mRNA 编码的 Cas13 作为泛呼吸道抗病毒药物

• 批准号: 10637171
• 负责人: PHILIP J SANTANGELO
• 金额: $ 72.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-23 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637171
• 关键词: 2019-nCoV; Address; Animal Model; Antiviral Agents; Binding; Biotechnology; COVID-19 pandemic; Circulation; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; Conserved Sequence; Containment; Doctor of Philosophy; Dose; Down-Regulation; Enzymes; Formulation; Gene Transduction Agent; Goals; Hamsters; Human; In Vitro; Individual; Infection; Influenza; Influenza A virus; Influenza B Virus; Innate Immune Response; Messenger RNA; Modeling; Mucous Membrane; Mus; Nature; Nebulizer; Organ; Pathogenesis; Pharmaceutical Preparations; Predisposition; Publications; Qualifying; RNA; RNA Degradation; Resistance; Respiratory System; Ribonucleases; Rodent; SARS coronavirus; SARS-CoV-2 transmission; Safety; Seasons; Surface; Time; Universities; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; antiviral drug development; co-infection; compare effectiveness; drug development; drug efficacy; fluorescence imaging; functional outcomes; genomic RNA; improved; in vitro Assay; in vivo; innovation; lung basal segment; mRNA delivery; mortality; mouse model; neutralizing antibody; nuclease; pathogen; resistance mutation; respiratory; respiratory pathogen; respiratory virus; small molecule; success; transcriptome sequencing; transmission process; ultra high resolution; vaccine efficacy; viral RNA

Project Summary There are over 200 viruses known to infect humans and they contribute to 6.6% of global mortality. We have approximately 91 drugs for 10 viral species and vaccines for only 16. Reassortment and antigenic changes pose challenges to vaccine efficacy; this has clearly been demonstrated during the COVID pandemic. Current drug development is focused on small molecules and neutralizing antibodies, which require high doses or frequent re-dosing to obtain functional outcomes and have also been challenged by antigenic changes. Thus, it is crucial to address the need for higher efficiency and broader spectrum antivirals. To address this need we are proposing an entirely different paradigm for antiviral development, an mRNA-encoded activatable RNase, Cas13, as a platform for a pan-respiratory treatment. Cas13 represents a programmable RNase that can directly target and degrade multiple viral messenger or genomic RNA. Synthetic mRNA is being used to deliver the RNase, as it allows for transient, non-viral delivery, with an improved safety profile over other gene therapy vectors1. Given achieving pan-respiratory results with a single mRNA-encoded Cas13 based drug is not trivial, critical steps towards that goal can be achieved by focusing on the three most impactful respiratory viruses in circulation, RSV, influenza and SARS-CoV-2. To date, our team was the first to demonstrate efficacy of mRNA-encoded Cas13 in vitro and in vivo via nebulizer-based lung delivery against influenza in the mouse model and SARS- CoV-2 in the hamster model in our recent publication in Nature Biotechnology. In order to achieve one drug for RSV, influenza and SARS-CoV-2 there are important questions/challenges that will need to be met. Thus, we will determine the optimal Cas13 species for multiple respiratory pathogens and investigate the mechanism of action of Cas13 for each virus. We will also demonstrate single drug efficacy against RSV, influenza and SAR- CoV-2 in vivo in mouse and hamster models, given as treatments for the individual viral infections, during co- infection (influenza and SAR-CoV-2), and to mitigate transmission of SARS-CoV-2.

项目概要 已知有 200 多种病毒可感染人类，它们造成全球死亡率的 6.6%。我们有 大约 91 种药物针对 10 种病毒，而疫苗仅针对 16 种。重配和抗原变化造成 疫苗功效面临的挑战；这一点在新冠肺炎疫情期间得到了清楚的证明。目前药物 开发重点是小分子和中和抗体，需要高剂量或频繁 重新给药以获得功能结果，并且也受到抗原变化的挑战。因此，至关重要的是 以满足对更高效率和更广谱抗病毒药物的需求。为了满足这一需求，我们建议 一种完全不同的抗病毒开发范例，一种 mRNA 编码的可激活 RNase，Cas13，作为 泛呼吸治疗平台。 Cas13代表一种可编程的RNase，可以直接靶向和 降解多种病毒信使或基因组 RNA。合成 mRNA 用于传递 RNase，因为它 允许瞬时、非病毒传递，与其他基因治疗载体相比，安全性更高1。给定 使用单一 mRNA 编码的 Cas13 药物实现泛呼吸结果并非易事，而是关键步骤 可以通过关注循环中三种最具影响力的呼吸道病毒来实现这一目标， RSV、流感和 SARS-CoV-2。迄今为止，我们的团队是第一个证明 mRNA 编码的功效的团队 Cas13 在小鼠模型和 SARS 模型中通过基于雾化器的肺部递送在体外和体内对抗流感 我们最近在《自然生物技术》杂志上发表的文章中介绍了仓鼠模型中的 CoV-2。为了实现一种药物 RSV、流感和 SARS-CoV-2 存在需要解决的重要问题/挑战。因此，我们 将确定多种呼吸道病原体的最佳Cas13物种并研究其机制 Cas13 对每种病毒的作用。我们还将展示针对 RSV、流感和 SAR 的单一药物功效 小鼠和仓鼠模型体内的 CoV-2，作为个体病毒感染的治疗方法，在 感染（流感和 SAR-CoV-2），并减轻 SARS-CoV-2 的传播。