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

好了！ 项目摘要 流行病学家很早就认识到了以高危“核心群体”为目标的巨大潜力 有效控制传染病的“超级传播者”。对于艾滋病毒/艾滋病，高危行为，如在人 世卫组织注射毒品(PWID)和女性性工作者，建立导致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中的艾滋病毒爆发(Peter等人。NEJM 2016年； Campbell等人。JID 2017)。未能针对这些群体采取有针对性的疾病控制措施，大大削弱了 遏制艾滋病毒暴发和减少发病率的能力(艾滋病规划署全球艾滋病更新，2019年)。不幸的是， 尽管有巨大的潜在好处，但针对这些高危群体的疾病控制措施往往不是 在实践中是可行的，因为实现它们的成本和努力都很高(Maxman自然，2018年)。 为了接触到这些关键人群，该项目将利用基因驱动技术(National 科学院，2016年报告)。基因驱动是一种人工合成的结构，设计用于在KEY内扩展 从基因上取代病原体，从而控制疾病的传播。现代基因驱动- 基于Cas9-目前正在布基纳法索、巴西和其他地区进行控制疟疾的现场试验。这个 HIV基因驱动的理论基础是我们广泛的初步研究表明，原型HIV基因 DRIVE已经在人源化的小鼠身上证明了有效性，并可能构成单一给药干预 具有很高的抗性屏障(Tanner等人，《自然》杂志，在综述中)。流行病学分析表明，基因 驱动将通过与艾滋病毒相同的风险因素在高危艾滋病毒感染人群中传播。特别是，对于 注射用药在PWID-当多个HIV变种共同传播时-基因驱动平台将是独一无二的 适合于克服现有的目标障碍，准确地接触到那些最难到达的超级传播者。 这项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身上进行测试 从PWID中提取的细胞在原代细胞和人源化小鼠中验证初步的体外效果。第二, 已建立的非人类灵长类(NHP)艾滋病毒感染模型将用于检测安全性(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 在国家卫生政策中，使用注射毒品的人群使用动物到动物的传播模型。最后，基于我们的 积极的人源化小鼠数据和现有的临床试验先例(例如，NCT03617198，一项为期24周的ATI试验 这是基于人性化小鼠数据批准的)我们将启动一项早期I/0期临床干预试验 在临终艾滋病毒队列(最后一份礼物队列，吸毒人群)中。这项试验将测试该药的安全性和有效性 HIV基因驱动在降低设定点病毒血症中的作用。总体而言，这些研究将推动基因驱动的发展 针对PWID高危人群的技术。最终，艾滋病毒基因驱动可以补充和发挥作用 一个整合现有基因治疗方法(例如RNAi、eCD4等)的平台，从而产生 有针对性的控制的效率效益，而不需要识别和接触高危群体的成本和挑战。

! 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.