A defend and destroy approach to curing HIV

一种防御和破坏治疗艾滋病毒的方法

基本信息

批准号：
9254596
负责人：
David T Scadden
金额：
$ 228.57万
依托单位：
HARVARD UNIVERSITY
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：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9254596
关键词：
AIDS/HIV problem Ablation Adoption Advocate Alleles American Animals Anti-Retroviral Agents Antibodies Area Autologous Autologous Transplantation Berlin Biometry Blood CCR5 gene CD34 gene CD8-Positive T-Lymphocytes CRISPR/Cas technology Cell Communication Cells Clinical Clinical Data Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Development Effector Cell Engineering Engraftment European Gene-Modified Genes Genetic Goals HIV HIV Infections HIV resistance HIV-1 Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homing Homologous Transplantation Human Immune system Infection Laboratories Liver Lymphopoiesis Maps Measures Messenger RNA Methodology Modification Morbidity - disease rate Mus Mutation Patients Pharmaceutical Preparations Pharmacology Preparation Procedures Protocols documentation Research Personnel Research Project Grants Resistance Safety Services Stem cell transplant Stem cells System Technology Testing Therapeutic Thymus Gland Time Toxic effect Transplantation Viral Viral reservoir authority base cell type clinical development cohort conditioning cost design experience fetal gene transplantation for gene therapy genetically modified cells genome editing humanized mouse in vivo meetings mouse model multidisciplinary novel novel strategies pre-clinical preclinical development public health relevance stem cell niche success synergism

项目摘要

DESCRIPTION (provided by applicant): This proposal seeks to achieve a durable cure of HIV through the use of autologous gene-modified cells in a 'Defend and Destroy' approach. Our central premise is that autologous cells can be used to eradicate HIV if they are 1. Genetically rendered HIV-uninfectable, and, 2. Enhanced in their activity by specific measures to destroy viral reservoirs. We have therefore assembled a team of investigators with complementary areas of expertise to execute the following specific aims: Specific aim 1: Utilize novel genetic modification technologies to engineer HIV- resistant immune systems with enhanced ability to destroy viral reservoirs. (Derrick Rossi, PI) This takes advantage of expertise in the Rossi lab with the CRISPR- Cas9 genome editing system and modified-mRNA technology. Specific aim 2: Enhance engraftment of gene modified hematopoietic stem cells with reduced toxicity, niche sparing conditioning of the host to minimize morbidity and costs without compromising targeting of viral reservoirs. (David Scadden, PI) Specific aim 3: Test approaches for viral control and vira reservoir depletion in a HIV-infected and anti-viral treated 'humanized' mouse model. (Todd Allen, PI) Specific aim 4: Pre-clinical development of HIV-resistant hematopoietic stem cells. (CRISPR Therapeutics, Rodger Novak, PI) Each aims maps to a project and the projects are supported by two cores: A. Administration and Biostatistics, and, B. Humanized mouse core generating, treating and analyzing BLT mice infected with HIV and treated with triple drug anti-retroviral therapy. Each of the four Specific Aims described above could be conducted independently as a scientifically significant research project. However, it is the synergy achieved through the coordinated accomplishment of these aims that will enable the testing of a multi-pronged strategy for eradicating HIV infection. Testing of such a complex set of strategies, which together represent the platform for a "Defend and Destroy" approach to curing HIV infection, would simply not be possible if any one project were conducted out of the context of the other three. Thus, it is only the concerted execution of this package of four Projects, supported by two critical Cores, that will facilitate testing of the proposed, highly novel strateg for curing HIV.

描述（由适用提供）：该提案旨在通过在“防御和破坏”方法中使用自体基因改性细胞来实现艾滋病毒的持久治疗。我们的中心前提是，如果自体细胞为1。遗传呈现的HIV-无感染，则可以用来放射性hiv，而2。通过破坏病毒储层的特定措施增强了其活性。因此，我们已经组建了一个研究人员团队具有完善的专业知识领域，以执行以下特定目标：具体目标1：利用新型的遗传修饰技术来设计具有破坏病毒储量的能力增强的抗HIV抗HIV免疫系统。（Derrick Rossi，pi）通过CRISPR-CAS9基因组编辑系统和修改MRNA技术，这利用了Rossi实验室的专业知识。特定目标2：增强基因改性的造血干细胞的植入，毒性降低，宿主的利基保留条件，以最大程度地减少发病率和成本，而不会损害病毒储层的靶向。（David Scadden，PI）特定目标3：在感染了HIV和抗病毒治疗的“人源化”小鼠模型中，病毒控制和Vira储层耗竭的测试方法。（托德·艾伦（Todd Allen），pi）特定目标4：抗HIV抗造血干细胞的临床前发育。（CRISPR疗法，Rodger Novak，PI）每个目标都瞄准了一个项目，并且这些项目得到了两个核心：A。给药和生物统计学以及B. B.人源化的小鼠核心产生，治疗和分析了感染HIV的BLT小鼠，并用三重药物抗逆转录病毒治疗治疗。上述四个特定目标中的每一个都可以独立地作为一项科学重要的研究项目。但是，这是实现的协同作用通过对这些目标的协调成就，可以测试消除艾滋病毒感染的多管齐下策略。如果在其他三个项目的背景下进行任何一个项目，则对这种复杂的一组策略进行了测试，这些策略共同代表了“防御和破坏”治疗艾滋病毒感染方法的平台。这只是由两个关键核心支持的四个项目包的一致执行，这将有助于测试拟议中的，高新颖的治疗艾滋病毒策略。