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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要对于 COVID-19，注射吸毒者 (PWID) 已被确定为高暴露风险人群 SARS-CoV-2（导致 COVID-19 的病毒），因为它们无家可归或无家可归的风险增加监禁——与疾病传播率增加和 HIV-1 合并感染有关的情况。鉴于 SARS-CoV-2 疫苗可能需要 12-24 个月才能问世，因此医疗需求尚未得到满足可能遏制普通人群和难以到达的地区爆发 COVID-19 的对策此外，我们对高风险人群（尤其是吸毒者）的认识存在根本性差距。这些高危吸毒者人群中 SARS-CoV-2 感染和发病机制的研究表明，SARS- CoV-2 感染并消耗 T 淋巴细胞，许多感染 HIV 的吸毒者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 CD4+ T 细胞耗竭，因此，SARS-CoV-2 感染可能。加速 AIDS 的临床进展，或者 HIV+ 吸毒者中的 SARS-CoV-2 感染可能会恶化 COVID-19 临床症状导致死亡风险升高，因此，HIV 阳性注射吸毒者的死亡风险可能升高。在这些注射吸毒者人群中，减少 T 细胞消耗将是非常有效的。有利于阻止临床进展，并且可能是一个可行的长期治疗目标。该补充提案旨在重新利用现有技术来快速开发基因驱动疗法（GDT） SARS-CoV-2 的候选者并量化其在患者 T 细胞中体外干扰和传播的广度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（见家长）奖）和针对寨卡病毒（ZIKV）的 GDT，证明 GDT 概念可以重新用于其他用途基于对 HIV 和 ZIKV 的初步广泛研究，中心假设是一种假定的病毒。 SARS-CoV-2 GDT 耗尽了所有致病病毒基因，可以针对与野生型 SARS 相同的细胞 CoV-2（包括T淋巴细胞），竞争细胞内资源，降低SARS CoV-2病毒载量和发病机制，从而作为单次给药治疗的 GDT 对策的基本原理。 SARS CoV-2 的研究基于人源化小鼠中 HIV-1 的大量数据以及 FDA 会议的积极结果。通过两个具体目标实现我们的目标：(i) 设计 SARS-CoV-2 GDT 候选药物（通过调整现有的 (ii) 测试 SARS CoV-2 GDT 候选药物对患者 T 细胞的保护作用墨西哥蒂华纳的 HIV+ 吸毒者队列虽然 GDT 方法存在固有风险，但单次给药。治疗方法将非常有益，特别是对于治疗难以接触的高危吸毒者群体。无论 GDT 在防止 T 细胞耗竭方面是否成功，本文提出的研究都将有通过分析 SARS-CoV-2 感染如何影响 HIV+ 的 T 淋巴细胞，具有广泛的基础意义这些研究还将验证一种有潜力的新型医疗对策。快速部署应对新的病毒威胁。