LABORATORY ANIMAL STUDIES IN GENE THERAPY

基因治疗中的实验动物研究

• 批准号: 3069103
• 负责人: JOHN H WOLFE
• 金额: $ 8.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3069103
• 关键词: bone marrow transplantation; cats; complementary DNA; disease /disorder model; dogs; gene therapy; genetic manipulation; mucopolysaccharidosis; recombinant DNA

It is proposed to investigate the use of somatic cell gene therapy for the correction of genetic diseases using domestic animals as test systems. A large number of models of human genetic disease have been discovered in domestic animals and characterized in detail at the Univ. of Pennsylvania School of Veterinary Medicine. Among these diseases are the mucopolysaccaridoses (MPS) which are recessive and result from defects in single genes encoding enzymes involved in the degradation of glycosaminoglycans (GAGs). Breeding colonies of MPS cats and dogs have been established. Thus, diseased animals are immediately available as test subjects. MPS cells can endocytose exogenous normal enzyme and degrade GAGs. Therefore, the experimental strategy will be to construct retrovirus vectors containing cDNA copies of normal genes, introduce the vectors by infection into bone marrow cells, and autologously transplant the cells to repopulate the donor/patient with cells producing normal enzyme. The sponsors, Drs. D. Patterson and M. Haskins, are members of the University-wide NIH Human Genetics Center and have extensive interactions with scientists working on genetic diseases in man. However, there is no one at the Veterinary School who has the expertise in molecular genetics who can concentrate on constructing and testing the vectors that are needed to perform the proposed experiments. Therefore, it is proposed that the candidate, Dr. John Wolfe, receive the necessary further training in molecular genetics to enable him to conduct these experiments. Therefore, it is proposed that the candidate, Dr. John Wolfe, receive the necessary further training in molecular genetics to enable him to conduct these experiments. He is a graduate of the NIH Veterinary Medical Scientist Training Program where he received training in immunogenetics, retrovirology and protein chemistry and is now an Exxon Fellow in Molecular Genetics at Sloan-Kettering Institute. Thus, he has training in most of the techniques needed to do the proposed experiments. A leading researcher on retroviral vectors, Dr. E. Gilboa of Princeton Univ., has agreed to collaborate with him on the construction and evaluation of the vectors. Dr. R. Schmikel of the Medical School who is the principle investigator of the Genetics Center and Dr. R. Brinster of the Veterinary School who is a leading investigator in the technology of gene transfer into embryo cells have agreed to participate in Dr. Wolfe's training. It is anticipated that the proposed training in recombinant DNA technology will enable him to establish a laboratory at the Veterinary School that will concentrate on the molecular aspects of genetic diseases and gene therapy using the domestic animal models at test systems.

建议研究体细胞基因治疗的用途 使用家畜作为纠正遗传疾病的方法 测试系统。 大量人类遗传病模型 已在家畜中发现，其特征在于 大学的详细信息。宾夕法尼亚兽医学院的。 这些疾病包括粘多糖贮积症 (MPS) 是隐性的，是由编码单基因的缺陷引起的 参与糖胺聚糖降解的酶 （GAG）。 MPS 猫和狗的繁殖群体已 已确立的。 因此，患病动物可立即作为 测试对象。 MPS细胞可以内吞外源正常酶 并降解 GAG。 因此，实验策略将是 构建含有正常基因 cDNA 拷贝的逆转录病毒载体 基因，通过感染将载体引入骨髓细胞， 并自体移植细胞以重新填充 具有产生正常酶的细胞的供体/患者。 赞助商，博士。 D. Patterson 和 M. Haskins 是以下组织的成员 国立卫生研究院 (NIH) 人类遗传学中心 与研究遗传疾病的科学家进行广泛的互动 在人身上。 然而，兽医学校没有人 拥有分子遗传学方面的专业知识，可以专注于 构建和测试执行所需的向量 所提议的实验。 因此，建议 候选人约翰·沃尔夫博士接受必要的进一步培训 分子遗传学使他能够进行这些实验。 因此，建议候选人 John Wolfe 博士， 接受分子遗传学方面必要的进一步培训 使他能够进行这些实验。 他是一名毕业生 NIH 兽医医学科学家培训计划，他在那里 接受过免疫遗传学、逆转录病毒学和蛋白质方面的培训 化学，现在是埃克森美孚分子遗传学研究员 斯隆-凯特琳研究所。 因此，他接受过大部分的训练 进行所提出的实验所需的技术。 领先的 逆转录病毒载体研究员，普林斯顿大学 E. Gilboa 博士， 已同意与他合作进行建设和 向量的评估。 医学院R. Schmikel博士 他是遗传学中心的首席研究员，博士。 兽医学院的 R. Brinster，首席研究员 在将基因转移到胚胎细胞的技术方面已达成一致 参加Wolfe博士的培训。 预计 拟议的重组 DNA 技术培训将使他能够 在兽医学校建立一个实验室 专注于遗传疾病和基因的分子方面 在测试系统中使用家畜模型进行治疗。