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: 10782797
• 负责人: Leor S Weinberger
• 金额: $ 18.71万
• 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/10782797
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Biological Assay; Brazil; Burkina Faso; Cells; Clinical; Clinical Trials; Communicable Diseases; Complement; Country; County; Data; Development; Disease; Disease Outbreaks; Drug usage; Engineering; Epidemic; Epidemiologist; Epidemiology; Failure; Genes; Gifts; HIV; HIV Infections; HIV therapy; HIV/AIDS; In Vitro; Incidence; Indiana; Injecting drug user; Intervention; Intervention Trial; Location; Malaria; Measures; Modeling; Modernization; Nature; Patients; Phase; Population; RNA Interference; Reporting; Resistance; Resource-limited setting; Risk Factors; Rural; Safety; Testing; United States National Academy of Sciences; Update; Variant; Viremia; cohort; cost; disorder control; end of life; female sex worker; gene drive system; gene therapy; genotoxicity; high risk; high risk behavior; high risk population; humanized mouse; immunogenicity; injection drug use; nonhuman primate; novel; pathogen; pre-exposure prophylaxis; prototype; safety testing; synthetic construct; transmission process; Acquired Immunodeficiency Syndrome; Animals; Biological Assay; Brazil; Burkina Faso; Cells; Clinical; Clinical Trials; Communicable Diseases; Complement; Country; County; Data; Development; Disease; Disease Outbreaks; Drug usage; Engineering; Epidemic; Epidemiologist; Epidemiology; Failure; Genes; Gifts; HIV; HIV Infections; HIV therapy; HIV/AIDS; In Vitro; Incidence; Indiana; Injecting drug user; Intervention; Intervention Trial; Location; Malaria; Measures; Modeling; Modernization; Nature; Patients; Phase; Population; RNA Interference; Reporting; Resistance; Resource-limited setting; Risk Factors; Rural; Safety; Testing; United States National Academy of Sciences; Update; Variant; Viremia; cohort; cost; disorder control; end of life; female sex worker; gene drive system; gene therapy; genotoxicity; high risk; high risk behavior; high risk population; humanized mouse; immunogenicity; injection drug use; nonhuman primate; novel; pathogen; pre-exposure prophylaxis; prototype; safety testing; synthetic construct; transmission process

Project Summary Epidemiologists have long recognized the immense potential of targeting high-risk ‘core groups’ and ‘superspreaders’ to efficiently control infectious diseases. For HIV/AIDS, high-risk behaviors, such as in persons who inject drugs (PWID) and female sex workers, establish core groups of superspreaders that drive disease spread, exemplified by the HIV outbreak among PWID in Scott County, Indiana (Peters et al. NEJM 2016; Campbell et al. JID 2017). Failure to target disease-control measures to these groups substantially weakens the ability to contain HIV outbreaks and reduce incidence (UNAIDS Global AIDS Update, 2019). Unfortunately, despite tremendous potential benefits, targeting disease-control measures to these high-risk groups is often not feasible in practice due to the high cost and effort of reaching them (Maxmen Nature, 2018). To reach these key populations, this project will capitalize on gene drive technologies (National Academy of Sciences, 2016 report). Gene drives are synthetic constructs engineered to expand within key populations, genetically displace the pathogen, and thereby control disease spread. Modern gene drives— based upon Cas9—are currently in field trials to control malaria in Burkina Faso, Brazil, and other locations. The rationale for an HIV gene drive is based upon our extensive preliminary studies showing that prototype HIV gene drives have demonstrated efficacy in humanized mice and could constitute single-administration interventions with a high barrier to resistance (Tanner et al, Nature, in review). Epidemiological analyses indicate that gene drives would spread through high-risk HIV-infected groups via the same risk factors as HIV. In particular, for injection drug use in PWID—when multiple HIV variants co-transmit—gene-drive platforms would be uniquely suited to overcome existing targeting obstacles and reach precisely those hardest-to-reach superspreaders. This proposal will test a prototype gene drive for HIV. First, prototype gene drives will be tested in patient cells from PWID to validate preliminary in vitro efficacy in primary cells and humanized mice. Second, established non-human primate (NHP) models of HIV infection will be used to assay safety (immunogenicity and genotoxicity), efficacy, and the potential of gene drives to expand and transmit within HIV-infected PWID populations using an injection drug use animal-to-animal transmission model in NHPs. Finally, based on our positive humanized-mouse data and existing clinical trial precedents (e.g., NCT03617198, a 24-week ATI trial that was approved based on humanized-mouse data) we will initiate an early Phase-I/0 clinical intervention trial in an end-of-life HIV cohort (Last Gift cohort, a drug-use population). This trial will test safety and efficacy of the HIV gene drive in lowering set-point viremia. Overall, these studies will propel development of gene drive technologies to target high-risk PWID populations. Ultimately, HIV gene drives could complement and serve as a platform to incorporate existing gene-therapy approaches (e.g. RNAi, eCD4, etc.), thereby yielding the high- efficiency benefits of targeted control without the cost and challenge of identifying and reaching high-risk groups.

项目摘要 流行病学家长期以来已经认识到针对高风险“核心群体”和 “超级公民”有效控制传染病。对于艾滋病毒/艾滋病，高风险行为，例如人 谁注射药物（PWID）和女性性工作者，建立驱动疾病的超级驱动者的核心群体 传播，以印第安纳州斯科特县的PWID之间的艾滋病毒爆发为例（Peters等人NEJM 2016； 坎贝尔等。 JID 2017）。未能针对疾病控制措施对这些组的措施实质上削弱 遏制艾滋病毒爆发并降低发病率的能力（UNAIDS Global AIDS更新，2019年）。很遗憾， 尽管有巨大的潜在益处，但针对这些高风险群体的疾病控制措施通常不是 在实践中可行的，因为付出了高昂的成本和努力（Maxmen Nature，2018年）。 为了达到这些关键人群，该项目将利用基因驱动技术（国家 科学院，2016年报告）。基因驱动器是经过设计的合成结构，可在密钥内扩展 种群，基因置换病原体，从而控制疾病扩散。现代基因驱动器 - 基于CAS9 - 目前正在现场试验中，以控制巴西布基纳法索和其他地点的疟疾。这 HIV基因驱动的基本原理是基于我们广泛的初步研究，表明原型HIV基因 驱动器在人性化的小鼠中表现出效率，并且可能构成单次管理干预措施 具有高阻力障碍（Tanner等人，自然，综述）。流行病学分析表明基因 驱动器将通过与艾滋病毒相同的危险因素通过高风险的艾滋病毒感染组传播。特别是 PWID中的注射药物使用（多个HIV变体共染色）将是独特的 适合克服现有的目标障碍，并确切地达到那些最难到达的超级传播者。 该建议将测试HIV的原型基因驱动器。首先，原型基因驱动器将在患者中进行测试 从PWID到验证原代细胞和人源化小鼠的初步体外效率的细胞。第二， HIV感染的已建立的非人类灵长类动物（NHP）模型将用于测定安全性（免疫原性和 遗传毒性），效率和基因驱动力在HIV感染的PWID中扩展和传播的潜力 使用注射药物使用动物到动物传输模型的种群在NHP中。最后，基于我们 阳性人性化鼠标数据和现有的临床试验先例（例如NCT03617198，24周的ATI试验 根据人性化鼠标数据批准了这一点）我们将启动早期I/0临床干预试验 在临终艾滋病毒队列中（最后一次礼物队列，药物使用人群）。该试验将测试安全性和效率 HIV基因驱动降低了固定点病毒血症。总体而言，这些研究将推动基因驱动的发展 针对高风险PWID人群的技术。最终，艾滋病毒基因驱动器可以补充并充当 一个融合现有基因疗法方法（例如RNAi，ECD4等）的平台，从而产生了高 目标控制的效率益处，而无需识别和到达高风险群体的成本和挑战。