Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors

泡沫病毒载体治疗白细胞粘附缺陷

• 批准号: 8256628
• 负责人: David W Russell
• 金额: $ 48.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256628
• 关键词: Adverse effects; Affect; Allogeneic Bone Marrow Transplantation; Animal Model; Animals; Bacterial Infections; Biological Assay; Blood Cells; Bone Marrow Purging; Busulfan; CD11 Antigens; CD34 gene; Canis familiaris; Cells; Child; Clinical; Clinical Trials; Data; Development; Disease; Enhancers; Funding; Future; Genes; Genetic Transcription; Grant; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hereditary Disease; Human; Human Spumavirus; ITGB2 gene; In Vitro; Infection; Integrins; LMO2 gene; Lentivirus Vector; Leukocyte Adhesion Deficiency; Leukocytes; Life; Location; Longevity; Malignant Neoplasms; Maps; Measures; Methods; Modeling; Monitor; Mus; Mutation; Oncogene Activation; Patients; Phase I Clinical Trials; Production; Proto-Oncogenes; Provirus Integration; Proviruses; Regimen; Research; Retroviral Vector; Safety; Site; Spumavirus; Stem cells; Surface; Survival Rate; Symptoms; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Transplantation; United States National Institutes of Health; Vertebral column; Viral Vector; Virus; Whole-Body Irradiation; Work; base; cell type; cellular transduction; conditioning; design; gene therapy; genetic element; genotoxicity; graft vs host disease; immortalized cell; infant death; leukemia; meetings; monocyte; neutrophil; pre-clinical; preclinical efficacy; preclinical safety; prevent; promoter; research study; success; vector; vector-induced

DESCRIPTION (provided by applicant): Leukocyte adhesion deficiency (LAD) is one of many diseases with the potential to be cured by hematopoietic stem cell (HSC) gene therapy. In LAD, mutations in the CD18 gene prevent expression in blood cells that then fail to migrate into tissues, resulting in life-threatening bacterial infections. LAD has been treated with allogeneic bone marrow transplantation, but there can be significant regimen-related toxicity and graft-versus-host disease, and many patients lack an HLA-matched donor. While there have been notable successes in treating some genetic diseases with stem cell gene therapy, proto-oncogene activation by the viral vectors used can cause malignancies. Thus there is a need for less genotoxic vectors that efficiently transduce HSCs. Foamy Virus (FV) vectors are an alternative retroviral vector system that is less genotoxic than other types of retroviral or lentiviral vectors. Prior research showed that the canine model of LAD (CLAD) could be cured by FV vectors expressing CD18. The experiments proposed here will develop and test FV vectors to treat human LAD. These vectors will be analyzed for efficacy and safety in human cells, including hematopoietic cells from LAD patients. The possibility that specific genetic elements such as insulators are responsible for the reduced genotoxicity of FV vectors will be explored. A GMP grade stock of the vector intended for clinical use will be prepared. The CLAD dogs previously treated with FV vectors will also be followed for 5 additional years to provide long-term data in a large animal model. The proposed experiments will generate essential preclinical data for an LAD gene therapy trial and they are crucial for the future development of the promising FV vector system. PUBLIC HEALTH RELEVANCE: Here we will develop a cure for leukocyte adhesion deficiency (LAD) based on stem cell gene therapy with foamy virus (FV) vectors, with direct relevance for the treatment of human LAD. This would be the first clinical trial of FV vectors, and if safe and successful, it would support their use in treating many hematopoietic diseases.

描述（由申请人提供）：白细胞粘附缺乏症（LAD）是许多疾病之一，有可能通过造血干细胞（HSC）基因疗法治愈。在LAD中，CD18基因中的突变阻止了血细胞中未能迁移到组织中的表达，从而导致威胁生命的细菌感染。 LAD已接受了同种异体骨髓移植治疗，但可能存在与方案有关的毒性和移植物与宿主疾病的重要相关性，许多患者缺乏HLA匹配的供体。 尽管用干细胞基因疗法治疗某些遗传疾病取得了显着的成功，但所使用的病毒载体的原始癌基因激活可能会引起恶性肿瘤。因此，需要较少有效传递HSC的遗传毒性载体。泡沫病毒（FV）载体是一种替代逆转录病毒载体系统，其遗传毒性比其他类型的逆转录病毒或慢病毒载体。先前的研究表明，LAD（clad）的犬模型可以通过表达CD18的FV矢量来治愈。此处提出的实验将开发和测试FV向量以治疗人类LAD。这些载体将进行分析，以了解人类细胞的功效和安全性，包括来自LAD患者的造血细胞。将探索诸如绝缘子等特定的遗传元素负责降低FV载体的遗传毒性的可能性。将准备用于临床使用的载体的GMP级库存。先前用FV载体治疗的外壳狗还将遵循另外5年，以在大型动物模型中提供长期数据。提出的实验将为LAD基因治疗试验生成必需的临床前数据，它们对于有希望的FV载体系统的未来发展至关重要。 公共卫生相关性：在这里，我们将基于使用泡沫病毒（FV）载体的干细胞基因治疗来制定白细胞粘附缺乏症（LAD），并且与人类LAD的治疗直接相关。这将是FV载体的第一次临床试验，如果安全和成功，它将支持他们在治疗许多造血疾病中的使用。