Treatment of Leukocyte Adhesion Deficiency by Foamy Virus Vectors

描述(由申请人提供)：白细胞黏附缺陷(LAD)是许多疾病之一，有可能通过造血干细胞(HSC)基因治疗而治愈。在LAD中，CD18基因的突变阻止了血细胞的表达，然后血细胞无法迁移到组织中，导致威胁生命的细菌感染。LAD已接受异基因骨髓移植治疗，但可能会出现明显的方案相关毒性和移植物抗宿主病，而且许多患者缺乏匹配的供者。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著的成功，但由所用病毒载体激活的原癌基因可能会导致恶性肿瘤。因此，需要基因毒性较低的载体来有效转导HSCs。泡沫病毒(FV)载体是一种替代的逆转录病毒载体系统，与其他类型的逆转录病毒或慢病毒载体相比，其遗传毒性较小。已有研究表明，表达CD18的Fv载体可治愈犬LAD模型。本文提出的实验将开发和测试FV载体来治疗人类LAD。这些载体将被分析在人类细胞中的有效性和安全性，包括来自LAD患者的造血细胞。我们将探讨特定的遗传因素，如绝缘体，可能是导致FV载体遗传毒性降低的原因。将准备用于临床的GMP级载体库存。之前接受FV载体治疗的包衣狗还将被跟踪5年，以提供大型动物模型的长期数据。所提出的实验将为LAD基因治疗试验产生必要的临床前数据，并对未来有前景的FV载体系统的发展至关重要。 公共卫生相关性：在这里，我们将开发一种基于泡沫病毒(FV)载体的干细胞基因疗法的白细胞黏附缺陷(LAD)的治疗方法，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，它将支持它们用于治疗许多血液系统疾病。

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.