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，以治疗白细胞粘附缺乏症（LAD）。在LAD中，CD18基因中的突变阻止了白细胞（白细胞）迁移到组织中，从而导致威胁生命的细菌感染。通过表达CD18的载体转导的自体造血干细胞（HSC）的移植可以治愈该疾病。然而，人类和大动物HSC难以有效地转导，并且已经证明基于鼠白血病病毒（MLV）的载体通过激活附近的细胞原始癌基因而引起白血病。 FV是逆转录病毒，基于它们的向量能够有效地将基因传递给HSC。它们不是致病性的，因此FV载体可能比其他类型的逆转录病毒载体更安全。在这里，FV矢量将用于将犬CD18基因传递给犬LAD（clad）的狗的HSC。然后将这些HSC移植到包裹犬中，在那里它们将分化为表达CD18的成熟血细胞。如果获得了足够的CD18水平，则移植的狗应在临床上改善并避免因感染而提早死亡。数据将用于确定带有FV载体的基因转移到犬HSC中的效率。整合位点分析将确定有多少不同的转导的细胞克隆有助于血液形成，以及特定克隆是否有选择性扩展。长期将遵循移植的动物，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调理方案。将评估使用不同启动子的FV矢量。将将FV载体与表达CD18的类似慢病毒载体进行比较，以确定LAD的HSC基因治疗的最佳类型。这些实验将确定FV载体是否可以有效地将基因转移到犬骨髓干细胞上，以及表达CD 18的FV载体是否可以治愈clad。这可能导致为LAD以及其他遗传或获得的血液疾病的新疗法发展，这可以改善许多美国人的健康。如果证明是安全有效的，则可以在拟议的实验中测试的FV矢量在人类临床试验中使用以治疗LAD。