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: 10377987
• 负责人: Leor S Weinberger
• 金额: $ 94.5万
• 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/10377987
• 关键词: AIDS/HIV problem; 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; 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; base; 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.

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