Genetic protection of hematopoietic stem cells for stable HIV control

造血干细胞的基因保护以稳定艾滋病毒控制

• 批准号: 8410026
• 负责人: Dong Sung An
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410026
• 关键词: Adverse effects; Antiviral Agents; Binding; Bone Marrow; Bone Marrow Transplantation; CCR5 gene; CD34 gene; Capsid; Cell Transplants; Cell membrane; Cell surface; Cells; Chemokine (C-C Motif) Receptor 5; Chimeric Proteins; Cytoprotection; Development; Disease; Disease remission; Engineering; Escape Mutant; FDA approved; Gene Expression; Genes; Genetic; Goals; Growth; HIV; HIV Fusion Inhibitors; HIV Infections; HIV drug resistance; HIV therapy; HIV-1; Hematopoietic; Hematopoietic stem cells; Human; Human Engineering; Immune; In Vitro; Infection; Interphase Cell; Knowledge; Lead; Lentivirus Vector; Life; Life Cycle Stages; Liver; Long-Term Effects; Lymphoid; Mediating; Membrane; Membrane Fusion; Mus; Organ; Organoids; Patients; Pharmaceutical Preparations; Positioning Attribute; Prevention; Production; Proteins; Public Health; Reagent; Research; Resistance; Resistance development; Safety; Site; Staging; Stem cells; Testing; Therapeutic; Therapeutic Studies; Thymus Gland; Transcript; Transgenes; Transplantation; Tropism; United States National Institutes of Health; Variant; Viral; Viral Load result; base; cellular transduction; cost; cost effective; design; gene therapy; in vivo; inhibitor/antagonist; innovation; interest; mouse model; novel; prevent; reconstitution; small hairpin RNA; stem; therapeutic gene; vector

DESCRIPTION (provided by applicant): Hematopoietic stem/progenitor cell (HSPC) based gene therapy holds great promise to provide long-term control of HIV with a single treatment. Like HAART, it is essential to combine multiple drugs to effectively suppress HIV and prevent drug resistant HIV escape mutants. The overall hypothesis of this proposal is that stable introduction of highly potent combinations of anti-HIV genes capable of inhibiting multiple early and late steps of HIV viral lifecycle into HSPC will provide lifelong protection from HIV infection The safety and efficacy of anti-HIV HSPC gene therapy strategies, including inhibition of HIV, lowering of viral load and selective growth advantage of protected cells and prevention of resistance will be evaluated in the recently developed human bone marrow, liver and thymus (BLT) transplanted mouse model. Specific aims are 1) To develop novel multi-pronged anti-HIV gene therapeutic lentiviral vectors and characterize therapeutic reagents to inhibit HIV infection in HSPC and their progeny in vitro 2) To determine the long-term anti-gene expression and stable control of HIV through genetically engineered human HSPC transplant in the BLT mouse model. The approach is innovative because it focuses on novel HIV-1 target HSPC protection and the development of novel potent, broad-range early stage and late stage anti-HIV combinations, maximizing the potential to HIV replication not only in HSPC but also all potential target cells. The proposed research is significant because the results may ultimately lead to an innovative, more effective, more convenient, less toxic, safe and more cost effective way of controlling HIV infection than is currently available. The long-term goal is to advance HSPC based gene therapy research and make rapid progress towards providing a new therapy that leads to stable control of HIV by a single treatment. PUBLIC HEALTH RELEVANCE: Our proposed research will positively impact public health with the development of an anti-HIV gene therapy by blocking the multiple early and late stages of the HIV infection. Ultimately, HIV infection will be controlled with a single treatment by protecting the hematopoietic stem cells and their progeny. This research will provide significant knowledge towards the long-term goal of the NIH "HIV cure."

描述（由申请人提供）：基于造血干细胞/祖细胞（HSPC）的基因治疗有望通过单一治疗长期控制 HIV。与HAART一样，必须联合使用多种药物才能有效抑制HIV并防止产生耐药性HIV逃逸突变体。该提案的总体假设是，将能够抑制 HIV 病毒生命周期多个早期和晚期步骤的高效抗 HIV 基因组合稳定引入 HSPC，将为 HIV 感染提供终生保护。抗 HIV HSPC 基因治疗策略的安全性和有效性，包括抑制 HIV、降低病毒载量和受保护细胞的选择性生长优势以及预防耐药性，将在 最近开发出人类骨髓、肝脏和胸腺（BLT）移植小鼠模型。具体目标是 1) 开发新型多管齐下的抗 HIV 基因治疗慢病毒载体，并表征治疗试剂在体外抑制 HSPC 及其后代中的 HIV 感染 2) 通过基因工程人类 HSPC 移植在 BLT 小鼠模型中确定 HIV 的长期抗基因表达和稳定控制。该方法具有创新性，因为它专注于新的 HIV-1 靶标 HSPC 保护，以及开发新型有效、广泛的早期和晚期抗 HIV 组合，最大限度地提高 HIV 复制的潜力，不仅在 HSPC 中，而且在所有潜在的靶细胞中。拟议的研究意义重大，因为结果可能最终带来一种比目前可用的创新、更有效、更方便、毒性更小、安全且更具成本效益的控制艾滋病毒感染的方法。长期目标是推进基于 HSPC 的基因治疗研究，并在提供一种通过单一治疗稳定控制 HIV 的新疗法方面取得快速进展。 公共健康相关性：我们提出的研究将通过阻断艾滋病毒感染的多个早期和晚期阶段来开发抗艾滋病毒基因疗法，从而对公共健康产生积极影响。最终，通过保护造血干细胞及其后代，通过单一治疗即可控制艾滋病毒感染。这项研究将为美国国立卫生研究院“治愈艾滋病毒”的长期目标提供重要的知识。