AAV Delivered CCR5 Blockade for Prevention of Mother-to-Child HIV Transmission.

AAV 提供 CCR5 阻断以预防 HIV 母婴传播。

• 批准号: 10670864
• 负责人: Jonah B. Sacha
• 金额: $ 21.88万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-25 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670864
• 关键词: Adherence; Adult; Age; Animal Model; Animals; Antibodies; Antibody Therapy; Area; Binding; Blocking Antibodies; Breast Feeding; Breastfed infant; CCR5 gene; CD4 Positive T Lymphocytes; Characteristics; Child; Clinical Trials; Dependovirus; Developing Countries; Development; Dose; Drug Delivery Systems; Drug Interactions; Epidemic; Gene Expression; Gene Transduction Agent; Growth; HIV; HIV Infections; HIV-1; Health Priorities; Human; Human Milk; Immunoglobulin G; Individual; Infant; Infection; Infection Control; Infection prevention; Injections; Intramuscular; Macaca; Macaca mulatta; Mediating; Modality; Modeling; Monitor; Mother-to-child HIV transmission; Newborn Infant; Oral; Performance; Perinatal; Persons; Pharmaceutical Preparations; Phenocopy; Phenotype; Plasma; Prevention; Preventive measure; Prophylactic treatment; Recording of previous events; Regimen; Reporting; Resistance development; Resource-limited setting; Resources; Risk; Route; Safety; Serious Adverse Event; Surface; Technology; Testing; Therapeutic; Time; Toxic effect; Variant; Vertical Disease Transmission; Vertical Transmission; Viral Load result; Viral Physiology; Virus; Work; adeno-associated viral vector; antenatal care; antiretroviral therapy; cost; delivery vehicle; drug development; drug resistant virus; extracellular; gene delivery system; gene therapy; human disease; immunogenic; immunogenicity; immunoprophylaxis; in vivo; inhibitor; neutralizing antibody; novel; peripheral blood; pre-clinical; pre-exposure prophylaxis; prevent; prophylactic; side effect; simian human immunodeficiency virus; small molecule; tissue tropism; transgene expression; transmission process; viral resistance

PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Furthermore, preventing HIV infection in newborns via mother-to-child transmission (MTCT) continues to be a major objective in areas with limited resources for antenatal care. While antiretroviral treatment (ART) has been critical in reducing transmission of HIV-1, it is not without risk, including toxicity of ART drugs in newborns and the development of drug resistant viral variants. Thus, there is an urgent need for safer preventative measures to eliminate MTCT of HIV-1. We have demonstrated that the CCR5-specific antibody Leronlimab can be used as an effective pre-exposure prophylaxis (PrEP) regimen in macaques. Here, we are proposing to utilize AAV- vectored Leronlimab to facilitate in vivo delivery of Leronlimab expression in infant macaques to prevent perinatal SHIV infection. In specific aim 1, we will determine the ability of AAV9-delivered Leronlimab to prevent acquisition of SHIV in newborn macaques. In aim 2, we will characterize the long-term performance of AAV9 gene therapy administered to newborn macaques. This work would provide a safe and viable alternative to prevent vertical transmission of HIV-1 and support direct in vivo delivery of anti-HIV prophylactic modalities in infants.

项目总结 鉴于目前感染艾滋病毒的人数是历史上最多的，遏制艾滋病毒流行仍是当务之急。 此外，通过母婴传播预防新生儿感染艾滋病毒仍然是一项重要工作。 主要目标是在产前护理资源有限的地区。虽然抗逆转录病毒治疗(ART)已经 对于减少艾滋病毒-1的传播至关重要，它并不是没有风险，包括抗逆转录病毒药物对新生儿和 抗药性病毒变种的开发。因此，迫切需要采取更安全的预防措施。 以消除HIV-1的母婴传播。我们已经证明了CCR5特异性抗体Leronlimab可以用于 作为一种有效的猕猴暴露前预防(PrEP)方案。在这里，我们建议使用AAV- 载体Leronlimab促进婴儿猕猴体内表达Leronlimab预防围产期 希夫病毒感染。在具体目标1中，我们将确定AAV9递送的Leronlimab防止获取的能力 新生猕猴体内的希夫病毒。在目标2中，我们将描述aav9基因治疗的长期效果。 给刚出生的猕猴注射。这项工作将提供一种安全可行的替代方案，以防止垂直 艾滋病毒-1的传播和支持在婴儿体内直接提供抗艾滋病毒预防方法。