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

项目摘要 流行病学家早就认识到，针对高危“核心群体”的巨大潜力， “超级传播者”有效控制传染病。对于艾滋病毒/艾滋病，高危行为，如在人 注射毒品（PWID）和女性性工作者，建立了推动疾病的超级传播者核心群体， 传播，例如印第安纳州斯科特县PWID中的HIV爆发（Peters等人NEJM 2016; 坎贝尔等人JID 2017）。未能针对这些群体采取疾病控制措施， 控制艾滋病毒爆发和降低发病率的能力（联合国艾滋病规划署全球艾滋病最新情况，2019年）。不幸的是， 尽管有巨大的潜在好处，但针对这些高危人群的疾病控制措施往往不是 在实践中可行，因为达到它们的成本和努力都很高（Maxmen Nature，2018）。 为了覆盖这些关键人群，该项目将利用基因驱动技术（国家 科学院，2016年报告）。基因驱动器是合成的构建体，其被设计成在关键区域内扩增， 在人群中，基因取代病原体，从而控制疾病的传播。现代基因驱动- 目前，基于Cas9的疫苗正在布基纳法索、巴西和其他地区进行实地试验，以控制疟疾。的 艾滋病毒基因驱动的基本原理是基于我们广泛的初步研究，表明原型艾滋病毒基因 驱动器已在人源化小鼠中证明有效，并可构成单次给药干预措施 具有高耐药性屏障（坦纳等人，《自然》，评论中）。流行病学分析表明， 驱动器将通过与艾滋病毒相同的风险因素在高风险艾滋病毒感染群体中传播。特别是 在PWID中使用注射药物-当多个HIV变体共传播时-基因驱动平台将是唯一 适合克服现有的目标障碍，并准确地达到那些最难达到的超级传播者。 该提案将测试艾滋病毒的基因驱动原型。首先，原型基因驱动将在患者中进行测试， 细胞，以验证在原代细胞和人源化小鼠中的初步体外功效。第二、 已建立的HIV感染的非人灵长类动物（NHP）模型将用于测定安全性（免疫原性和 遗传毒性）、有效性以及基因驱动在HIV感染的PWID内扩展和传播的潜力 使用注射药物的人群在NHP中使用动物间传播模型。最后，根据我们的 阳性人源化小鼠数据和现有的临床试验先例（例如，NCT 03617198，一项为期24周的ATI试验 我们将启动早期I/0期临床干预试验 最后一份礼物队列（Last Gift cohort，一个药物使用人群）。该试验将测试 HIV基因驱动降低设定点病毒血症。总的来说，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，艾滋病毒基因驱动可以补充并作为 整合现有基因治疗方法（如RNAi、eCD 4等）的平台，从而产生高- 有针对性的控制的效率效益，而没有成本和挑战，确定和接触高风险群体。

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.