CRISPR for Cure

CRISPR 治愈

• 批准号: 10619015
• 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
• 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/10619015
• 关键词: Ablation; Acceleration; Achievement; Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Adenoviruses; Animal Model; B-Lymphocytes; Bar Codes; Basic Science; Binding; 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; 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; Institution; 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; Myelogenous; Myeloid Cells; Myelopoiesis; Outcome; PTPNS1 gene; Patients; Peripheral Blood Mononuclear Cell; Persons; Population; Positioning Attribute; Private Sector; Probability; Proviruses; Research; Residual state; Resource Allocation; Resources; Role; SIV; Safety; Sampling; Specificity; Standardization; Structure; Technology; Testing; Thrombopoietin; Toxicology; Up-Regulation; Viral; Viral reservoir; Viremia; Virus; Work; antiretroviral therapy; bioinformatics pipeline; cell killing; clinical investigation; cohort; collaboratory; community engagement; cytokine; design; exhaustion; experience; functional restoration; genetic approach; genome editing; high throughput screening; humanized mouse; immune activation; implementation barriers; improved; in vivo; industry partner; innovation; innovative technologies; insight; latent infection; latent virus activation; manufacture; manufacturing capabilities; 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

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）大大降低了艾滋病毒疾病的发病率和死亡率，但它未能 消除病毒储存库。治疗中断导致潜伏病毒活化和体内病毒血症反弹 周迫切需要新的策略来根除潜伏感染并增强免疫系统 导致ART停止后病毒反弹的持续、持久控制。 20-035 Martin Delaney Collaboratories for HIV Cure Research，我们现在提交申请， “CRISPR for Cure.“该计划的首要目标是利用CRISPR介导的基因组编辑， 增强免疫反应并直接消除HIV前病毒。我们组建了一个合作团队， 高度成就的基础和转化科学家与社区利益相关者和 一家小型生物技术公司开发基于CRISPR的疗法，直接针对HIV前病毒， 增强免疫反应。该研究计划由三个高度互动的研究组成 焦点（RF）将利用跨学科，创新和合作的研究方法与社区 和政府投入。RF 1将使用下一代测序和新型条形码病毒来定义HIV 水库和前病毒反弹的后生机制的影响。在RF 2中，我们将增强效应NK细胞 和CTL细胞功能和杀伤，并使用创新的基因组编辑限制靶细胞的病毒传播 战略布局RF 3将创建和测试下一代可诱导的多重CRISPR， 通过CD 4嗜性淋巴腺AAV 9递送用于根除HIV-1前病毒DNA特异性、效力和安全性 在动物模型中，其免疫细胞在RF 2中被修饰，并评估通用和 个性化CRISPR在体内消除有复制能力的病毒。除了共同关注 CRISPR技术，合作实验室将通过以下方式进行高度集成的实验议程： 条形码病毒在人源化小鼠中的共享使用和独特的 支持 MISTRG人源化小鼠， 人造血干细胞和祖细胞维持与骨髓生成;恒河猴 感染了新型SIV条形码化病毒;来自充分表征的组群的离体临床样品和其用途 将CRISPR有效地递送至携带来自人源化细胞的体内人源化动物模型。 患者来源的PBMC。这项全面的多学科计划的结果是由“CRISPR for 治愈” 的 合作实验室将加速使用基因编辑策略，以消除艾滋病毒感染， 停止抗逆转录病毒治疗后，患者的身体或病毒持续缓解。 从我们的私营部门合作伙伴，我们将处于有利地位，进一步GMP生产的发展， 未来的初步临床研究。