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（由申请人证明）：该提案旨在实现艾滋病毒的方法。执行以下特定目的的互补领域：具体目的1：利用1：利用新颖的遗传修饰技术来设计具有销毁病毒储量的能力增强的抗HIV艾滋病毒免疫系统。 CRISPR-CAS9基因组编辑系统和修饰的MRNA技术特定目标3：在感染HIV和抗病毒治疗的小鼠模型中的病毒控制和Vira储量的测试方法。生物群体和人性化的小鼠核心，分析用艾滋病毒感染的BLT小鼠，并用Trug的抗质膜治疗通过协调的成就，对消除艾滋病毒感染的多种策略进行了测试。另一个由两个关键核心支持的四个项目，这将有助于测试拟议中的高度新颖策略。