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: 8391684
• 负责人: David W Russell
• 金额: $ 53.06万
• 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/8391684
• 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; deep sequencing; 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.

描述（由申请人提供）：白细胞粘附缺陷（LAD）是许多有可能通过造血干细胞（HSC）基因疗法治愈的疾病之一。在 LAD 中，CD18 基因的突变阻止了血细胞的表达，从而导致血细胞无法迁移到组织中，从而导致危及生命的细菌感染。 LAD 已通过同种异体骨髓移植进行治疗，但可能存在明显的治疗相关毒性和移植物抗宿主病，而且许多患者缺乏 HLA 匹配的供体。 虽然干细胞基因疗法在治疗一些遗传性疾病方面取得了显着的成功，但所使用的病毒载体激活原癌基因可能会导致恶性肿瘤。因此，需要有效转导HSC的基因毒性较小的载体。泡沫病毒 (FV) 载体是另一种逆转录病毒载体系统，其基因毒性低于其他类型的逆转录病毒或慢病毒载体。先前的研究表明，表达CD18的FV载体可以治愈LAD（CLAD）的犬模型。这里提出的实验将开发和测试 FV 载体来治疗人类 LAD。这些载体将在人类细胞（包括 LAD 患者的造血细胞）中进行功效和安全性分析。将探讨诸如绝缘体等特定遗传元件导致 FV 载体遗传毒性降低的可能性。将制备供临床使用的 GMP 级载体库存。之前用 FV 载体治疗的 CLAD 狗还将被跟踪 5 年，以提供大型动物模型的长期数据。拟议的实验将为 LAD 基因治疗试验产生必要的临床前数据，它们对于有前途的 FV 载体系统的未来发展至关重要。