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.

项目摘要 已知有200多种感染人类的​​病毒，它们占全球死亡率的6.6％。我们有 仅16种病毒物种和疫苗的大约91种药物。 疫苗功效的挑战；这在库维德大流行期间清楚地证明了这一点。当前药物 开发集中于小分子和中和抗体，这些抗体需要高剂量或频繁 重新服用以获得功能结果，并受到抗原变化的挑战。因此，这是至关重要的 满足对更高效率和更广泛的抗病毒药的需求。为了满足我们提出的需求 抗病毒发育的完全不同的范式，一种mRNA编码的可活化RNase Cas13作为A 泛滥治疗的平台。 CAS13代表一个可编程的RNase，可以直接定位和 降解多个病毒信使或基因组RNA。合成mRNA被用于传递RNase， 允许瞬时非病毒递送，与其他基因疗法载体相比，安全概况的提高了1。给出 通过单个mRNA编码的基于CAS13的药物实现泛呼吸结果不是微不足道的关键步骤 通过关注流通中最有影响力的呼吸道病毒，可以实现这一目标 RSV，流感和SARS-COV-2。迄今为止，我们的团队是第一个展示mRNA编码功效的团队 CAS13在小鼠模型中通过雾化器基于雾化器的肺递送在体外和体内。 仓鼠模型中的COV-2在我们最近在《自然生物技术》中的出版物中。为了获得一种药物 RSV，流感和SARS-COV-2存在重要的问题/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 每种病毒的CAS13作用。我们还将证明针对RSV，流感和SAR-的单一药物功效 小鼠和仓鼠模型中的COV-2体内，作为单个病毒感染的治疗，在共同的过程中给予 感染（流感和SAR-COV-2），以及减轻SARS-COV-2的传播。