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

基本信息

批准号：
8703001
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
项目类别：
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/8703001
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 Escape Mutant FDA approved Gene Expression Genes Genetic Genetic Engineering 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

项目摘要

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.

描述（由申请人提供）：基于造血的茎/祖细胞（HSPC）基因疗法具有巨大的希望，可以通过单一治疗提供对HIV的长期控制。像Haart一样，必须结合多种药物以有效抑制HIV并防止耐药性HIV逃生突变体。该提案的总体假设是，能够抑制HIV病毒生命周期的多个早期和晚期的抗HIV基因高度有效组合的稳定引入将提供HIV感染的终生保护，以保护HSPC基因治疗策略的安全性和抑制性较低的抗体能力，包括对HIV的抑制和选择性的抑制，对抗HIV HSPC基因治疗策略的安全性和有效性，包括对病毒的影响和选择性的抑制，对病毒的限制和选择性的抑制作用，促进了对抗体的影响。最近开发的人骨髓，肝和胸腺（BLT）移植小鼠模型。具体目的是1）开发新型的多种抗HIV基因治疗性慢病毒载体，并表征治疗试剂以抑制HSPC的HIV感染及其在体外的后代2）确定通过基因工程的HSPC Transplant in Blt Mouss中的HEV对HIV的长期抗基因表达和稳定的HIV控制。该方法具有创新性，因为它专注于新型HIV-1靶标HSPC保护以及新型有效的，宽范围的早期和晚期抗HIV组合的发展，不仅在HSPC中，而且在所有潜在的靶细胞中都最大程度地提高了HIV复制的潜力。拟议的研究很重要，因为结果可能最终导致创新，更有效，更方便，毒性更少，安全和更具成本效益的控制HIV感染方式，而不是目前可用的。长期目标是提高基于HSPC的基因疗法研究，并在提供一种新的疗法方面取得快速进步，从而通过一种治疗来稳定地控制HIV。