Anti-HIV Gene Therapy: Defend and Attack

抗 HIV 基因疗法：防御与攻击

基本信息

批准号：
8899031
负责人：
IRVIN S.Y. CHEN
金额：
$ 225.61万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899031
关键词：
Ablation Acquired Immunodeficiency Syndrome Address Allogenic Animal Model Behavior Berlin Biological Process Blood Bone Marrow Bone Marrow Purging CCR5 gene Cell Transplants Cells Cellular biology Clinic Clinical Clinical Trials Collaborations Complex Conduct Clinical Trials Development Disease Donor person Engineered Gene Engraftment Gene Delivery Gene-Modified Genes Genetic Engineering Goals Grant HIV HIV Infections HIV-1 Hematopoietic Human Immunity Immunology Immunotherapeutic agent Immunotherapy Infection Knowledge Lentivirus Vector Life Macaca mulatta Malignant Neoplasms Modeling Monitor Mus Pathogenesis Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Procedures Progenitor Cell Engraftment Publishing Reagent Research Research Personnel Resistance Resistance development Running Stem cell transplant Stem cells T-Lymphocyte Testing Therapeutic Thioguanine Transgenes Transplantation Treatment Efficacy Viral Work Yang base career cell behavior cellular engineering chimeric antigen receptor combinatorial conditioning design experience gene therapy gene therapy clinical trial genetic selection high risk immune function improved in vivo inhibitor/antagonist killings knowledge base leukemia macrophage meetings member mouse model new technology nonhuman primate novel phase I trial pre-clinical preclinical study progenitor programs public health relevance reconstitution small hairpin RNA small molecule stem stem cell biology success therapeutic development tumor vector

项目摘要

DESCRIPTION (provided by applicant): The hypothesis to be tested in this U19 program is that combining gene modifying reagents with different modes of action will have a significant impact on HIV-1 disease with the possibility of achieving a cure. We will build upon our previous extensive experience in anti-HIV-1 genetic therapies to both broaden our knowledge and develop new technologies that will result in lentiviral vector based anti-HIV-1 therapeutic development candidate(s). The plan is to develop 2 vectors, one for HSPC and one for T-cell transplant and file an IND for a Phase I clinical trial by the end of the grant term. The few gene-based therapies for HIV-1 disease that have been tested in the clinic have been focused on protecting the differentiated progeny T-cells and macrophages, principally through ablation or reduction of CCR5 expression. In the single remarkable case of the "Berlin patient", allogeneic transplant of CCR532 donor cells resulted in a functional cure without evidence for remaining HIV-1. Efforts to mimic this CCR5 ablation through transplant of gene-engineered cells has shown some success, but suffers from several roadblocks which we will address in this proposal. First, a universal limitation in stem cell transplant is the difficulty of achieving engraftment levels sufficient to provide therapeutic efficacy. We propose to address this fundamental issue by testing approaches to selectively enrich for repopulation of gene-modified hematopoietic stem/progenitor cells (HSPC) using genetic selection for engrafted cells. A second major issue, one faced by all HIV-1 therapies, is the development of resistance by HIV-1. As with the development of small molecule therapies for HIV-1 disease, gene therapies will also require effective combinations. As such, our corporate partner, Calimmune, Inc., is currently testing in humans, T-cell and HSPC genetic therapy using CCR5 knockdown (shRNA1005) combined with a transmembrane fusion inhibitor (C46). Here, we propose to add a third reagent, a chimeric antigen receptor (CAR) recognizing HIV-1 infected cells, delivered by adoptive T-cell immunotherapy. T-cell immunotherapy with tumor specific CARs has proven to be effective against cancer in early human studies. While a CAR was tested years ago in humans for HIV-1 disease and found to be safe, it suffered from a number of limitations, now better understood, and to be addressed here. Finally, HSPC and T-cell transplants are complex biological processes that require a thorough understanding of repopulation by thousands of functionally diverse stem, progenitor, or mature cells. Each of the project leaders has had extensive experience working not only with HIV-1, but also in general stem cell biology and its applications to HIV-1 disease. The breadth of expertise ranges from vector and transgene development (Chen, An, Kitchen, Symonds), development and use of animal models for HSPC biology (Kitchen, An, Chen), anti-HIV-1 immune function (Yang, Kitchen), understanding of HSPC behavior (Chen) to Phase I and II clinical trial implementation (Symonds).

描述（由适用提供）：在本U19程序中要检验的假设是，将基因修饰试剂与不同的作用模式相结合将对HIV-1疾病产生重大影响，并有可能实现治愈方法。我们将基于我们以前在抗HIV-1基因疗法方面的丰富经验，以扩大我们的知识并开发新技术，从而导致基于慢病毒载体的抗HIV-1抗HIV-1治疗发展候选候选者（S）。该计划是开发2个向量，一个用于HSPC，一个用于T细胞移植，并在授予期结束时为I期临床试验提交IND。在临床中测试的少数基于基因的HIV-1疾病疗法一直集中在保护分化的进度的T细胞和巨噬细胞上，主要是通过消融或减少CCR5表达。在“柏林“患者”的单一显着情况下，对CCR532供体细胞的同种异体移植导致功能性治愈，而没有证据表明剩余HIV-1的努力。努力通过基因工程细胞的移植来模仿这种CCR5消融，这表现出了一些成功，但是我们将在该棘手的范围内陷入困境。足以提供治疗效率的水平。基因疗法还将需要有效的组合，我们的公司合作伙伴Calimmune，Inc。目前正在使用CCR5敲低（SHRNA1005）与跨膜融合抑制剂（C46）一起在人类，T细胞和HSPC基因治疗中进行测试。在这里，我们建议添加第三个试剂，即通过自适应T细胞免疫疗法传递的HIV-1感染细胞的嵌合抗原受体（CAR）。在早期人类研究中，用特定于肿瘤的汽车的T细胞免疫疗法已被证明有效地抵抗癌症。虽然几年前在人类中接受过HIV-1疾病的汽车进行了测试，但发现它是安全的，但它遭受了许多局限性，现在可以更好地理解并在此处解决。最后，HSPC和T细胞移植是复杂的生物学过程，需要对数千种功能上多样化的茎，祖细胞或成熟细胞进行透彻了解重生。每个项目领导者都有丰富的经验，不仅与HIV-1一起工作，而且在一般的干细胞生物学及其在HIV-1疾病中的应用。专业知识的广度范围从向量和转型开发（Chen，An，厨房，Symonds），用于HSPC生物学的动物模型（厨房，AN，Chen），抗HIV-1免疫学功能（Yang，厨房），HSPC行为（CHEN）到I期和II期临床试验实施（Symonds）。