Treatment Leukocyte Adhesion Deficiency by Foamy Virus

泡沫病毒治疗白细胞粘附缺陷

• 批准号: 7128279
• 负责人: David W Russell
• 金额: $ 37.23万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128279
• 关键词: CD antigens; CD34 molecule; DNA damage; Retroviridae; T lymphocyte; autosomal recessive trait; biotechnology; cell population study; disease /disorder model; dogs; gene therapy; genetic promoter element; hematopoietic tissue transplantation; immunodeficiency; leukemia; leukocyte adhesion molecules; longitudinal animal study; neutrophil; nonhuman therapy evaluation; polymerase chain reaction; provirus; stem cell transplantation; therapy adverse effect; therapy design /development; transfection /expression vector; virus integration

DESCRIPTION (provided by applicant): This proposal will develop foamy virus (FV) vectors for the treatment of leukocyte adhesion deficiency (LAD). In LAD, mutations in the CD18 gene prevent the migration of white blood cells (leukocytes) into tissues, resulting in life-threatening bacterial infections. Transplantation of autologous hematopoietic stem cells (HSCs) transduced by CD18-expressing vectors could cure this disease. However, human and large animal HSCs are difficult to transduce efficiently, and integrating vectors based on murine leukemia virus (MLV) have been shown to cause leukemia by activating nearby cellular proto-oncogenes. FVs are retroviruses and vectors based on them are able to efficiently deliver genes to HSCs. They are not pathogenic so FV vectors may be safer than other types of retroviral vectors. Here FV vectors will be used to deliver the canine CD18 gene to the HSCs of dogs with canine LAD (CLAD). These HSCs will then be transplanted into CLAD dogs, where they will differentiate into mature blood cells that express CD18. If adequate CD18 levels are obtained, the transplanted dogs should improve clinically and avoid an early death due to infections. The data will be used to determine the efficiency of transferring genes into canine HSCs with FV vectors. Integration site analysis will establish how many different transduced cell clones contributed to blood formation, and whether there was selective expansion of particular clones. The transplanted animals will be followed long-term to look for potential side effects, including the development of leukemia. Different conditioning regimens used to promote engraftment of transplanted cells will be tested. FV vectors that use different promoters will be evaluated. FV vectors will be compared to similar lentiviral vectors that express CD18 to determine the best type of vector for HSC gene therapy of LAD. These experiments will determine if FV vectors can efficiently transfer genes to canine bone marrow stem cells, and if FV vectors expressing CD 18 can cure CLAD. This could lead to the development of new treatments for LAD, as well as other genetic or acquired blood diseases, which could improve the health of many Americans. If shown to be safe and effective, the FV vectors tested in the proposed experiments could then be used in human clinical trials to treat LAD.

描述（由申请人提供）： 该提案将开发泡沫病毒（FV）载体用于治疗白细胞粘附缺陷（LAD）。在 LAD 中，CD18 基因突变会阻止白细胞迁移到组织中，从而导致危及生命的细菌感染。移植由表达 CD18 的载体转导的自体造血干细胞 (HSC) 可以治愈这种疾病。然而，人类和大型动物造血干细胞很难有效转导，基于鼠白血病病毒（MLV）的整合载体已被证明可以通过激活附近的细胞原癌基因而引起白血病。 FV 是逆转录病毒，基于它们的载体能够有效地将基因传递至 HSC。它们不具有致病性，因此 FV 载体可能比其他类型的逆转录病毒载体更安全。此处，FV 载体将用于将犬 CD18 基因传递至患有犬 LAD (CLAD) 的狗的 HSC。然后，这些 HSC 将被移植到 CLAD 狗体内，在那里它们将分化成表达 CD18 的成熟血细胞。如果获得足够的 CD18 水平，移植的狗的临床症状应该会有所改善，并避免因感染而过早死亡。这些数据将用于确定使用 FV 载体将基因转移到犬 HSC 中的效率。整合位点分析将确定有多少不同的转导细胞克隆有助于血液形成，以及是否存在特定克隆的选择性扩增。移植的动物将被长期跟踪，以寻找潜在的副作用，包括白血病的发展。将测试用于促进移植细胞植入的不同预处理方案。将评估使用不同启动子的 FV 载体。 FV载体将与表达CD18的类似慢病毒载体进行比较，以确定用于LAD的HSC基因治疗的最佳载体类型。这些实验将确定FV载体是否可以有效地将基因转移至犬骨髓干细胞，以及表达CD 18的FV载体是否可以治愈CLAD。这可能会导致针对 LAD 以及其他遗传性或获得性血液疾病的新疗法的开发，从而改善许多美国人的健康。如果被证明是安全有效的，那么在拟议的实验中测试的 FV 载体就可以用于治疗 LAD 的人体临床试验。