Autonomously deploying, co-evolving SARS-CoV-2 antiviral: a new paradigm for pandemic prevention

自主部署、共同进化的 SARS-CoV-2 抗病毒药物：预防大流行的新范例

基本信息

批准号：
10845714
负责人：
Robert Rodick
金额：
$ 199.71万
依托单位：
VXBIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10845714
关键词：
2019-nCoV Ablation Animal Model Antiviral Agents Antiviral Therapy Antiviral resistance Attenuated Vaccines Cells Communicable Diseases Complement Culicidae Development Disease Disease Progression Dose Elements Engineering Ethics Evolution Formulation Gene Mutation General Population Genetic Drift HIV Herd Immunity Immune Evasion Individual Infection Intervention Libraries Life Low Prevalence Molecular Mutate Mutation Parasites Pharmacologic Substance Phase I Clinical Trials Population Prevalence Property Proteins Randomized Resistance Resolution Rest Risk Factors Rodent Route SARS-CoV-2 antiviral SARS-CoV-2 variant Safety Starvation T-Lymphocyte Testing Theft Therapeutic Trans-Activators Transgenes United States National Institutes of Health Vaccination Vaccines Variant Viral Virus Zika Virus arms race conventional therapy cost design disorder control dosage economic impact epidemiological model first-in-human future pandemic high risk humanized mouse immunogenicity in vivo innovation insight large scale production manufacture medical countermeasure new pandemic nonhuman primate novel pandemic response particle pathogen pathogenic virus pressure prevent pandemics self-renewal superinfection synergism synthetic biology therapeutic evaluation transmission process vector viral resistance viral transmission virus genetics

项目摘要

PROJECT SUMMARY SARS-CoV-2, like all viruses, mutates and transmits; current medical countermeasures do not. This fundamental mismatch between dynamic viruses and our state-of-the-art static interventions means that vaccines and antiviral therapies often require frequent re-design and re-development, necessitating repeated (sometimes annual) resolutions to manufacturing and deployment challenges. Without fundamentally different forms of intervention to overcome this mismatch, future pandemics could rival or eclipse the catastrophic loss-of-life and economic impacts of SARS-CoV-2. To surmount the barriers thwarting current interventions, this proposal will engineer therapeutic molecular parasites of SARS-CoV-2 that can co-adapt and transmit among infected hosts. The key innovations of this approach are that these therapeutic parasites: (i) establish co-evolutionary arms races, co- evolving with wild-type virus to overcome resistance, (ii) replicate and self-renew, acting as single-administration therapies that circumvent compliance issues, and (iii) spread via the exact same risk factors and transmission routes as SARS-CoV-2—autonomously utilizing superspreaders to deploy the intervention—thereby circumventing manufacturing-at-scale and roll-out challenges. By design, these ‘piggybacking’ molecular parasites cannot replicate in uninfected hosts. Epidemiological models indicate that such molecular-parasite therapies would surmount the universal barriers to pandemic control and lower prevalence for many viruses below levels achievable by vaccination or antiviral therapy campaigns. The molecular rationale for developing molecular-parasite antivirals rests on ablating essential protein-encoding elements (i.e., trans-acting factors) to create conditionally replicating vectors that produce Therapeutic Interfering Particles (TIPs) when complemented in trans by wild-type virus superinfection. The crucial difference between TIPs and classical defective viral particles is that TIPs are engineered to have an R0 > 1—they efficiently mobilize, and transmit. As deletion variants, TIPs act as parasites, replicating only in virus-infected cells by stealing critical replication and packaging elements from the wild-type virus. By starving the wild-type pathogen of these critical elements, TIPs reduce wild-type pathogen levels. Critical feasibility precedents include that TIPs have been engineered to inhibit other viruses in vivo. Regulatory and ethical precedents include initial FDA clearances for HIV TIP Phase-I clinical trials supported by the NIH and DoD. This proposal will screen randomized synthetic libraries of SARS-CoV-2 variants to identify TIP candidates, test TIP efficacy and transmissibility in animal models, devise and test delivery and dosage formulations, and test tolerability, safety, and immunogenicity in a Phase-I clinical trial. The deliverable of this project will be the creation of a novel paradigm to counter SARS-CoV-2 and emerging pandemics by development and de-risking of an intervention that overcomes the universal barriers to infectious disease control.

项目摘要 SARS-COV-2与所有病毒，突变和传输一样；当前的医疗对策没有。这个基本动态病毒与我们最新的静态干预之间的不匹配意味着疫苗和抗病毒药物疗法通常需要经常重新设计和重新开发，需要反复（有时是年）制造和部署挑战的决议。没有根本不同的干预形式为了克服这一不匹配，未来的大流行可能会冒险或黯然失色 SARS-COV-2的影响。为了克服阻碍当前干预措施的障碍，该提案将设计 SARS-COV-2的治疗性分子寄生虫，可以在受感染宿主之间共同适应和传播。钥匙这种方法的创新是这些治疗性寄生虫：（i）建立共同进化的军备竞赛，共同用野生型病毒演变以克服抗药性，（ii）复制和自我更新，充当单次管理规避合规性问题的疗法，（iii）通过完全相同的风险因素和传播传播作为SARS-COV-2的路线 - 自主地利用超级公民部署干预措施 - 规避制造业和推出挑战。通过设计，这些“背包”分子寄生虫不能在未感染的宿主中复制。流行病学模型表明这种分子寄生虫疗法将为许多病毒的大流行控制和较低的患病率所带来的普遍障碍低于疫苗接种或抗病毒疗法运动可以达到的水平。发展的分子原理分子 - 寄生虫抗病毒药基于减少必需蛋白质编码元件（即跨作用因子）创建有条件复制的向量，以产生治疗性干扰颗粒（尖端）在通过野生型病毒末期转染中。尖端和经典缺陷病毒之间的关键差异粒子是该尖端的设计为R0> 1-它们有效地动员和传输。作为删除变体，尖端充当寄生虫，仅通过窃取关键复制和包装在病毒感染的细胞中复制野生型病毒的元素。通过挨饿这些关键元素的野生型病原体，尖端还原野生型病原体水平。关键可行性先例包括已设计提示以抑制其他体内病毒。监管和道德先例包括HIV尖端I期临床的初始FDA清除率 NIH和DOD支持的试验。该建议将筛选SARS-COV-2的随机合成库识别候选小费的变体，动物模型中的测试提示效率和传播，设计和测试交付在I期临床试验中，剂量公式以及测试耐受性，安全性和免疫原性。该项目的交付将是创建一个新颖的范式来对抗SARS-COV-2和新兴通过开发和脱离风险的干预措施来克服了传染性的普遍障碍疾病控制。