Anti-HIV Gene Therapy: Defend and Attack

抗 HIV 基因疗法：防御与攻击

• 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
• 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

 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(由申请人提供)：这个U19项目要检验的假设是，结合不同作用模式的基因修饰剂将对HIV-1疾病产生重大影响，并有可能实现治愈。我们将在过去抗HIV-1基因疗法丰富经验的基础上，拓宽我们的知识并开发新技术，从而开发基于慢病毒载体的抗HIV-1治疗候选药物(S)。该计划将开发两种载体，一种用于HSPC，另一种用于T细胞移植，并在赠款期限结束时提交IND进行I期临床试验。已在临床上测试的少数基于基因的治疗HIV-1疾病的方法一直专注于保护分化的后代T细胞和巨噬细胞，主要是通过消融或减少CCR5的表达。在一个引人注目的“柏林患者”案例中，异基因移植CCR5HIV-32供体细胞导致了功能性治愈，而没有证据证明残留的-1。通过移植基因工程细胞来模拟这种CCR5消融的努力已经取得了一些成功，但也遇到了几个障碍，我们将在本提案中解决这些障碍。首先，干细胞移植的一个普遍限制是很难达到足以提供治疗效果的植入水平。我们建议通过测试方法来解决这一根本问题，通过对移植细胞的遗传选择来选择性地丰富基因修饰的造血干细胞/祖细胞(HSPC)的再繁殖。所有艾滋病毒-1疗法都面临的第二个主要问题是艾滋病毒-1耐药性的产生。随着HIV-1小分子疗法的发展，基因疗法也需要有效的组合。因此，我们的合作伙伴加州免疫公司目前正在人类、T细胞和HSPC中测试使用CCR5基因敲除(ShRNA1005)和跨膜融合抑制物(C46)相结合的基因疗法。在这里，我们建议添加第三种试剂，识别HIV-1感染细胞的嵌合抗原受体(CAR)，通过过继T细胞免疫疗法传递。在早期的人类研究中，使用肿瘤特异性CARS的T细胞免疫疗法已被证明对癌症有效。虽然几年前，一辆汽车在人体上进行了HIV-1疾病的测试，发现是安全的，但它受到了一些限制，现在更好地理解了这些限制，这里要解决这些限制。最后，HSPC和T细胞移植是复杂的生物学过程，需要彻底了解数千个功能不同的干细胞、祖细胞或成熟细胞的再繁殖。每个项目负责人不仅在研究艾滋病毒-1方面，而且在一般干细胞生物学及其在艾滋病毒-1疾病中的应用方面都有丰富的经验。其专长范围广泛，从载体和转基因开发(Chen，An，Kitchen，Symonds)，HSPC生物学动物模型的开发和使用(Kitchen，An，Chen)，抗HIV-1免疫功能(Yang，Kitchen)，对HSPC行为的了解(Chen)，到第一阶段和第二阶段临床试验实施(Symonds)。