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

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

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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.

项目摘要由于目前有艾滋病毒的历史上有史以来大多数人，阻止艾滋病毒的流行仍然必须。抗逆转录病毒疗法（ART）限制了病毒复制，但没有治愈。因此，迫切需要通过消除病毒储层设计功能固化。蒂莫西·布朗（Timothy Brown），又名柏林病人和亚当 Castillejo，又名伦敦患者，在白血病相关，MHC匹配，同种异体后，治愈了HIV 来自CCR5缺乏供体的造血干细胞移植（HSCT）。而CCR5缺乏免疫系统可以明显地产生功能性HIV治疗，同种异体干细胞移植不可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可以通过占用所有可用的CCR5来模仿药理学上的CCR5供体分子。为了将leronlimab作为基因疗法选择，需要新的分娩方式。这里，我们建议利用我们的新颖的定向进化技术来生成针对T和B的AAV量细胞。这些新颖的AAV载体将在这里促进leronlimab表达的体内递送，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，并通过将这些治疗剂传递到相关的免疫细胞类型中来广泛中和抗体。具体 AIM 1，我们将生成并表征AAV轴承capsids，这些轴承夹构成t和b细胞，专门针对t和b细胞猕猴和人类。在AIM 2中，我们将通过交付这些新AAV的概念证明实用性 leronlimab至感染了Shiv感染的ART抑制猕猴，以确定是否可以使用功能治疗这种方法。这项工作将通过展示我们对HIV治疗机制的了解来扩大我们的知识基于长期抗体的竞争CCR5抑制，并建立一组新的AAV矢量来支持体内提供抗HIV治疗剂。