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.

尽管抗逆转录病毒疗法（ART）大大降低了HIV疾病的发病率和死亡率，但它未能消除病毒水库。治疗的中断导致潜在病毒和反弹病毒血症激活几周。迫切需要新颖的策略来放射性潜在感染并增强免疫系统停止艺术后，导致对病毒反弹的持续，持久的控制。响应rfa-ai- 20-035 Martin Delaney合作组织艾滋病毒治疗研究，我们现在提交题为申请 “ CRISPR治疗。”该程序的总体目标是使用CRIS介导的基因组编辑到增强免疫反应并直接消除HIV病毒。我们组建了一个合作团队高度成就的基本和翻译的科学家与社区利益相关者一起工作小型生物技术公司开发基于CRISPR的疗法，以直接针对HIV病毒和增强免疫学反应。研究计划完成了三项高度互动研究将与社区一起使用跨学科，创新和协作研究方法的FOCI（RF）和政府的意见。 RF1将使用下一代测序和新型的条形码病毒来定义HIV 水库和表观遗传机制对病毒反弹的影响。在RF2中，我们将增强效应子NK 和CTL细胞功能以及使用创新的基因组编辑杀死和限制靶细胞病毒扩散策略。 RF3将创建和测试下一代可诱导的多重CRISPR，并增加 CD4热带淋巴AAV9的特异性，效力和安全性用于HIV-1前病毒DNA的放射线在动物模型中，其免疫细胞在RF2中被修饰并评估了通用和普遍性的可能性个性化的CRISPR在体内消除复制能力的病毒。除了共同关注 CRISPRS技术，该协作将通过在人源化小鼠和独特的人性化病毒中共享条形码病毒支持 Misstrg人性化的小鼠差异化人造血茎和祖细胞维持和骨髓病；恒河猕猴感染了一种新型的SIV条形码病毒；来自良好表征的队列和使用的体内临床样品腺病毒有效地将CRISPRS提供给载有细胞的体内人性化动物模型患者来源的PBMC。 “ Crispr for for 治愈” 这合作组织，将加速使用基因编辑策略来消除艾滋病毒感染的停止抗逆转录病毒疗法后的身体或持续病毒缓解。从我们的私营部门合作伙伴那里，我们将在进一步的GMP制造开发方面处于良好状态，未来的初始临床研究。