A Gene Drive Therapy for HIV: single-administration intervention for high-risk groups

HIV基因驱动疗法：针对高危人群的单次给药干预

• 批准号: 10163412
• 负责人: Leor S Weinberger
• 金额: $ 18.9万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163412
• 关键词: 2019-nCoV; Acquired Immunodeficiency Syndrome; Award; Biological Assay; Bioreactors; CD4 Positive T Lymphocytes; COVID-19; Cell Survival; Cells; Clinical; Culicidae; Data; Disease Outbreaks; Engineering; Exhibits; Exposure to; General Population; Genes; Genomics; Goals; HIV; HIV therapy; HIV-1; Homelessness; Imprisonment; In Vitro; Individual; Infection; Injecting drug user; Intervention; Link; Lymphocyte; Medical; Mexico; Nature; Outcome; Parents; Pathogenesis; Pathogenicity; Patients; Population; Resources; Risk; Route; Symptoms; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Therapeutic; Vaccines; Validation; Viral; Viral Genes; Viral Load result; Viral Pathogenesis; Virus; Virus Replication; Zika Virus; antiretroviral therapy; base; cell killing; co-infection; cohort; disease transmission; high risk; high risk population; humanized mouse; medical countermeasure; meetings; mortality risk; mutant; novel; protective effect; success; transmission process

PROJECT SUMMARY/ABSTRACT For COVID-19, persons who inject drugs (PWID) have been identified as a population at high-risk of exposure to SARS-CoV-2 (the virus that causes COVID-19) because of their increased risk of homelessness or incarceration—situations linked to increased rates of the disease transmission and co-infection with HIV-1. Given that a SARS-CoV-2 vaccine is likely 12–24 months away, there is a critical unmet medical need for medical countermeasures that could contain COVID-19 outbreaks in the general population and in these difficult-to-reach high-risk populations such as PWIDs in particular. Moreover, there is a fundamental gap in our understanding of SARS-CoV-2 infection and pathogenesis in these at-risk PWID populations. Evidence indicates that SARS- CoV-2 infects and depletes T lymphocytes and many HIV-infected PWID have limited access to antiretroviral therapy and consequently exhibit pre-existing CD4+ T-cell depletion. Hence, SARS-CoV-2 infection could accelerate clinical progression to AIDS, or alternatively, SARS-CoV-2 infection in HIV+ PWID could exacerbate COVID-19 clinical symptoms leading to elevated risk of death. Thus, HIV+ PWID may be at elevated risk of death from SARS-CoV-2 infection. In these PWID populations, reducing T-cell depletion would be highly beneficial to halting clinical progression and may a viable long-term therapeutic goal. The specific objective of this supplement proposal is to repurpose existing technologies to rapidly develop a Gene Drive Therapy (GDT) candidate for SARS-CoV-2 and quantify its breadth of interference and transmission in vitro in patient T-cells from HIV+ PWID. This effort will build heavily off our recent success in engineering an HIV-1 GDT (see Parent Award) and a GDT against Zika Virus (ZIKV), demonstrating that the GDT concept can be repurposed for other viruses. The central hypothesis—based on extensive preliminary studies in HIV and ZIKV—is that a putative SARS-CoV-2 GDT, depleted of all the pathogenic viral genes, could target the same cells as wild-type SARS CoV-2 (including T lymphocytes), compete for intracellular resources, and reduce SARS CoV-2 viral load and pathogenesis, thereby serving as a single-administration therapeutic. The rationale for a GDT countermeasure for SARS CoV-2 is based on extensive data for HIV-1 in humanized mice and positive FDA meetings. We will achieve our objectives via two specific aims: (i) Engineer a SARS-CoV-2 GDT candidate (by adapting the existing Bioreactor platform); and (ii) Test the SARS CoV-2 GDT candidate's protective effect on patient T-cells from an HIV+ PWID cohort in Tijuana Mexico. While the GDT approach carries inherent risks, single-administration therapeutics would be highly beneficial particularly for treating difficult-to-reach, high-risk PWID populations. Regardless of the success of GDTs in protecting against T-cell depletion, the studies proposed here will have broad fundamental significance by assaying how SARS-CoV-2 infection impacts T lymphocytes from HIV+ PWID. These studies would also provide validation of a novel medical countermeasure with the potential to be rapidly deployed against new viral threats.

项目总结/摘要 对于COVID-19，注射毒品者（PWID）已被确定为高风险暴露人群 SARS-CoV-2（导致COVID-19的病毒），因为他们无家可归的风险增加， 监禁情况与疾病传播率和HIV-1合并感染率的增加有关。 考虑到SARS-CoV-2疫苗可能需要12-24个月的时间， 可能在普通人群和难以到达的地区控制COVID-19疫情的对策 尤其是高危人群，如PWID。此外，我们的理解存在着根本性的差距 SARS-CoV-2感染和发病机制在这些高危PWID人群。有证据表明，SARS- CoV-2感染并消耗T淋巴细胞，许多HIV感染的PWID获得抗逆转录病毒药物的机会有限 治疗，并因此表现出预先存在的CD 4 + T细胞耗竭。因此，SARS-CoV-2感染可能 加速艾滋病的临床进展，或者，HIV+ PWID中的SARS-CoV-2感染可能加剧 COVID-19临床症状导致死亡风险升高。因此，HIV+ PWID可能会增加 死于SARS-CoV-2感染。在这些PWID群体中，减少T细胞消耗将是高度重要的。 有益于阻止临床进展，并且可能是可行的长期治疗目标。的具体目标 该补充提案旨在重新利用现有技术，以快速开发基因驱动疗法（GDT） SARS-CoV-2的候选人，并量化其在患者T细胞中的体外干扰和传播宽度 HIV+ PWID这项工作将在很大程度上建立在我们最近成功设计HIV-1 GDT的基础上（见Parent Award）和针对寨卡病毒（ZIKV）的GDT，表明GDT概念可以重新用于其他目的。 病毒基于对HIV和ZIKV的广泛初步研究， SARS-CoV-2 GDT缺失了所有致病性病毒基因，可以靶向与野生型SARS相同的细胞 CoV-2（包括T淋巴细胞），竞争细胞内资源，减少SARS CoV-2病毒载量， 发病机制，从而用作单次施用治疗剂。GDT对策的基本原理 对SARS CoV-2的研究是基于HIV-1在人源化小鼠中的广泛数据和FDA会议的积极结果。我们将 通过两个具体目标实现我们的目标：（i）设计SARS-CoV-2 GDT候选人（通过调整现有的 生物反应器平台）;和（ii）测试SARS CoV-2 GDT候选物对来自急性呼吸道感染的患者T细胞的保护作用。 墨西哥蒂华纳的艾滋病毒+ PWID队列。虽然GDT方法具有固有的风险，但单一管理 治疗剂将是非常有益的，特别是对于治疗难以到达的、高风险的PWID人群。 无论GDT在防止T细胞耗竭方面是否成功，这里提出的研究都将具有 通过分析SARS-CoV-2感染如何影响HIV+ T淋巴细胞， PWID。这些研究还将提供一种新的医疗对策的验证， 快速部署以应对新的病毒威胁。