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CRISPR for Cure

CRISPR 治愈

基本信息

批准号：
10469440
负责人：
Tricia Helen Burdo
金额：
$ 480.77万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469440
关键词：
Achievement Acquired Immunodeficiency Syndrome Address Adenovirus Vector Adenoviruses Animal Model B-Lymphocytes Bar Codes Basic Science Biodistribution Biological Assay Biological Response Modifier Therapy Biotechnology CCR5 gene CRISPR/Cas technology Cell Maintenance Cell physiology Cells Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Complement DNA DNA Integration DNA Modification Process Development Disease Disease remission Education and Outreach Effector Cell Epigenetic Process Excision FCGR3B gene Funding Agency Future Genes Genetic Variation Genome Genomics Goals Government Granulocyte-Macrophage Colony-Stimulating Factor Growth Guide RNA HIV HIV Infections HIV-1 Hematopoietic stem cells Histopathology Human IL3 Gene Immune Immune response Immune system Immunodeficient Mouse Immunologics Infection Interleukin-15 Interleukin-6 Interruption Knock-out Knowledge Lymphoid Macaca Macaca mulatta Macrophage Colony-Stimulating Factor Measures Mediating Methods Modification Molecular Monitor Morbidity - disease rate Mouse Strains Mus Myeloid Cells Myelopoiesis Natural Killer Cells Outcome Patients Peripheral Blood Mononuclear Cell Persons Population Positioning Attribute Private Sector Proviruses Research Residual state Resources Role SIV Safety Sampling Specificity Standardization Structure T-Lymphocyte Technology Testing Thrombopoietin Up-Regulation Viral Viral reservoir Viremia Virus Work antiretroviral therapy base bioinformatics pipeline cell killing clinical investigation clinical toxicology cohort collaboratory community engagement cytokine design exhaustion experience functional restoration genetic approach genome editing high throughput screening humanized mouse immune activation implementation barriers in vivo industry partner innovation insight latent infection latent virus activation mortality mouse model multidisciplinary next generation next generation sequencing novel novel strategies operation pre-clinical programmed cell death protein 1 programs response synergism transcriptomics translational scientist viral DNA viral rebound virus genetics

项目摘要

While antiretroviral therapy (ART) has dramatically reduced HIV disease morbidity and mortality, it has failed to eliminate viral reservoirs. Interruption of treatment leads to activation of latent virus and rebound viremia within weeks. Novel strategies are urgently needed to eradicate latent infections and enhance the immune system leading to sustained, durable control of viral rebound following the cessation of ART. In response to RFA-AI- 20-035 Martin Delaney Collaboratories for HIV Cure Research, we now submit the application entitled "CRISPR for Cure." The overarching goal of this program is to use genome editing mediated by CRISPR to enhance immune responses and directly ablate HIV proviruses. We have assembled a collaborative team of highly accomplished basic and translational scientists working in tandem with community stakeholders and a small biotechnology company to develop CRISPR-based therapies to directly target the HIV provirus and to enhance immunological responses. The research program is comprised of three highly interactive research foci (RF) that will utilize interdisciplinary, innovative and collaborative research approaches with community and government input. RF1 will use next generation sequencing and novel barcoded viruses to define the HIV reservoir and the impact of epigenetic mechanisms on proviral rebound. In RF2, we will enhance effector NK and CTL cell function and killing and limit viral spread by target cells using innovative genome editing strategies. RF3 will create and test the next generation of inducible, multiplex CRISPR with increased specificity, potency and safety for delivery by CD4 tropic lymphoid AAV9 for eradication of HIV-1 proviral DNA in animal models whose immune cells are modified in RF2 and assess the possibility of both a universal and personalized CRISPR in eliminating replication competent virus in vivo. In addition to the shared focus on CRISPRs technology, the Collaboratory will undertake a highly integrated experimental agenda through the shared use of barcoded viruses in humanized mice and unique support MISTRG humanized mice that differentially human hematopoietic stem and progenitor cell maintenance and myelopoiesis;rhesus macaques infected with a novel SIV barcoded virus; ex vivo clinical samples from a well characterized cohort and the use of adenoviruses to efficiently deliver CRISPRs to an in vivo humanized animal model carrying cells from patient-derived PBMCs. The outcome of this comprehensive and multidisciplinary program by the “CRISPR for Cure” the Collaboratory, will accelerate the use of gene editing strategies towards eradication of HIV infection from body or sustained viral remission following cessation of antiretroviral therapy.With resources available from our private sector partner, we will be well positioned for further GMP manufacturing development, and future initial clinical investigations.

虽然抗逆转录病毒疗法 (ART) 显着降低了 HIV 疾病的发病率和死亡率，但未能消除病毒储存库。治疗中断会导致潜伏病毒激活并导致体内病毒血症反弹几周。迫切需要新策略来消除潜伏感染并增强免疫系统导致在停止 ART 后持续、持久地控制病毒反弹。回应 RFA-AI- 20-035 Martin Delaney 艾滋病毒治疗研究合作实验室，我们现在提交题为 “CRISPR 治愈”。该计划的总体目标是利用 CRISPR 介导的基因组编辑增强免疫反应并直接消除艾滋病毒原病毒。我们组建了一支协作团队成就卓著的基础和转化科学家与社区利益相关者和小型生物技术公司开发基于 CRISPR 的疗法，直接靶向 HIV 原病毒并增强免疫反应。该研究计划由三项高度互动的研究组成焦点 (RF) 将利用跨学科、创新和与社区合作的研究方法和政府投入。 RF1 将使用下一代测序和新型条形码病毒来定义 HIV 储存库和表观遗传机制对前病毒反弹的影响。在RF2中，我们将增强效应器NK 使用创新的基因组编辑，CTL 细胞发挥功能并杀死目标细胞并限制病毒传播策略。 RF3 将创建并测试下一代诱导型多重 CRISPR CD4 热带淋巴 AAV9 递送消除 HIV-1 前病毒 DNA 的特异性、效力和安全性在免疫细胞在 RF2 中进行修饰的动物模型中，并评估通用和通用的可能性个性化 CRISPR 消除体内具有复制能力的病毒。除了共同关注的焦点 CRISPR 技术，该合作实验室将通过以下方式开展高度综合的实验议程：条形码病毒在人源化小鼠中的共同使用和独特的支持 MSTRG 人源化小鼠具有差异人类造血干细胞和祖细胞维持和骨髓生成；恒河猴感染新型 SIV 条形码病毒；来自特征明确的队列的离体临床样本及其用途腺病毒可有效地将 CRISPR 传递至体内人源化动物模型，该模型携带来自患者来源的 PBMC。 “CRISPR for 治愈” 这合作将加速使用基因编辑策略来根除艾滋病毒感染停止抗逆转录病毒治疗后身体或持续病毒缓解。有可用资源通过我们的私营部门合作伙伴，我们将为进一步的 GMP 制造发展做好准备，并且未来的初步临床研究。