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发病率和死亡率，但它未能做到这一点