Evolving Novel AAV Vectors for Gene Therapy to Cure HIV

进化新型 AAV 载体用于基因治疗以治愈 HIV

基本信息

批准号：
10640060
负责人：
Aravind Asokan
金额：
$ 97.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-07 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640060
关键词：
Allogenic Animal Model Antibodies B-Lymphocytes Bar Codes Berlin Binding Blocking Antibodies CCR5 gene CRISPR/Cas technology Capsid Cells Clinical Trials Coupled Dependovirus Development Directed Molecular Evolution Disease remission Dose Engineering Ensure Epidemic Evolution Future Gene Delivery Gene Transduction Agent General Population Goals HIV HIV Infections Health Priorities Hematopoietic Stem Cell Transplantation Human Immune Immune system Individual Intramuscular Intravenous Knowledge Libraries London Macaca Macaca mulatta Mediating Modality Molecular Cloning Monitor Muscle Cells Patients Persons Phenocopy Phenotype Plasma Property Recording of previous events Role Safety Specificity Stem cell transplant Structure T-Lymphocyte Techniques Technology Testing Therapeutic Time Tissues Variant Viral Viral reservoir Virus Replication Work adeno-associated viral vector antiretroviral therapy cell type chimeric antigen receptor clinical development clinical translation clinically relevant cohort delivery vehicle design extracellular gene therapy global health human disease improved in vivo inhibitor interest leukemia neutralizing antibody novel pharmacologic pre-clinical purge simian human immunodeficiency virus small molecule therapeutically effective viral rebound

项目摘要

PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (ART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Timothy Brown, aka the Berlin Patient, and Adam Castillejo, aka the London patient, were cured of HIV following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5-deficient donor. While a CCR5-deficient immune system can demonstrably yield a functional HIV cure, allogeneic stem cell transplantation is not scalable to the general population and alternate approaches are needed. We have demonstrated that the CCR5-specific antibody Leronlimab can pharmacologically mimic a CCR5 deficient donor by occupying all available CCR5 molecules. In order to deliver Leronlimab as a gene therapy option, new delivery modalities are needed. Here, we are proposing to utilize our novel directed evolution technique to generate AAV vectors specific for T and B cells. These novel AAV vectors will facilitate in vivo delivery of Leronlimab expression here, but more importantly will support the future use of other anti-HIV approaches including CRISPR-Cas9, chimeric antigen receptors, and broadly neutralizing antibodies by delivering these therapeutics to the relevant immune cell type. In specific aim 1, we will generate and characterize AAV bearing capsids that target T and B cells specifically across both macaques and humans. In aim 2, we will demonstrate proof-of-concept utility of these new AAVs by delivering Leronlimab to SHIV-infected, ART suppressed macaques to determine if a functional cure can be achieved with this approach. This work would expand our knowledge of the mechanism of HIV cure by showing the utility of long-term antibody-based competitive CCR5 inhibition and establish a new set of AAV vectors to support in vivo delivery of anti-HIV therapeutics.

项目概要由于目前感染艾滋病毒的人数是历史上最多的，因此阻止艾滋病毒流行仍然势在必行。联合抗逆转录病毒疗法（ART）限制病毒复制，但不能治愈。因此，迫切需要通过消除病毒库来设计功能性治疗。蒂莫西·布朗（又名柏林病人）和亚当卡斯蒂列霍（Castillejo），又名伦敦患者，在接受白血病相关、MHC 匹配、同种异体治疗后，艾滋病毒被治愈来自 CCR5 缺陷供体的造血干细胞移植 (HSCT)。虽然 CCR5 缺陷免疫系统可以明显产生功能性艾滋病毒治愈，同种异体干细胞移植无法扩展到需要一般人群和替代方法。我们已经证明了 CCR5 特异性抗体 Leronlimab 可以通过占据所有可用的 CCR5 在药理学上模拟 CCR5 缺陷供体分子。为了将 Leronlimab 作为基因治疗选择，需要新的给药方式。这里，我们建议利用我们新颖的定向进化技术来生成 T 和 B 特异的 AAV 载体细胞。这些新型 AAV 载体将促进 Leronlimab 表达的体内传递，但更重要的是将支持未来使用其他抗 HIV 方法，包括 CRISPR-Cas9、嵌合抗原受体、通过将这些疗法传递给相关的免疫细胞类型来广泛中和抗体。具体来说目标 1，我们将生成并表征 AAV 携带衣壳，该衣壳专门针对 T 细胞和 B 细胞猕猴和人类。在目标 2 中，我们将通过交付来演示这些新 AAV 的概念验证实用性 Leronlimab 对感染 SHIV、ART 抑制的猕猴进行治疗，以确定是否可以实现功能性治愈这种方法。这项工作将通过展示以下方法的实用性来扩展我们对艾滋病毒治愈机制的了解：基于抗体的长期竞争性CCR5抑制并建立一套新的AAV载体来支持体内提供抗艾滋病毒治疗。