Center for Fetal Money Gene Transfer for HLB Diseases

HLB 疾病胎儿金钱基因转移中心

基本信息

批准号：
6452559
负责人：
Alice F Tarantal
金额：
$ 52.99万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The intent of this proposal is to establish a Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases. The immediate goal of this Center is to explore critical issues for in utero gene transfer in the rhesus monkey model, which closely simulates humans. We propose that performing gene transfer prenatally will provide the best opportunity for eliminating the pathology associated with many life-threatening congenital conditions because delivery of a corrective gene early is likely to prevent damage in organs or cells inaccessible later in life. However, before considering application for human fetuses, it is essential that issues such as cell tropism, levels and duration of gene expression, and safety be addressed in relevant animal models such as the monkey. Our first Objective is to investigate the efficiency of recombinant viral vector systems in transferring genes into fetal rhesus monkeys in vivo for cardiac, pulmonary, and hematopoietic disorders. In Objective 1, Specific Aim 1, we will explore the efficiency of transduction of two integrating viral vector systems, self-inactivating HIV-1-derived lentivirus and adeno-associated virus (AAV), using systemic and organ-targeting approaches. In these studies, constitutive and cell-specific promoters will be used, and we will transfer viral vector constructs into fetal monkeys at defined gestational ages and based on developmental milestones. In Specific Aim 2 of this Objective, we will determine whether immune responses are generated to transgene products and/or vectors, and confirm that organ structure and postnatal function is not altered as a result of our prenatal interventions. Our second Objective focuses on providing specialized services to NHLBI-funded investigators for fetal gene transfer for heart, lung, or blood diseases. In Objective 2, Specific Aim 1, we will provide our unique primate expertise, services, and resources to NHLBI-funded investigators who wish to evaluate their viral and non-viral gene transfer strategies in monkeys. In order to effectively provide these services, Specific Aim 2 of this Objective includes a plan for administrative/scientific oversight, a Scientific Advisory Committee, and outreach efforts for NHLBI-funded investigators. We propose that by establishing the Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases we will be able to explore the efficiency of gene transfer strategies as they emerge, fully investigate the potential effects of gene transfer on the fetus, infant, and mother, and significantly advance the field of gene therapy for future human application.

描述（由申请人提供）：该提案的目的是建立一个胎猴基因中心心脏、肺和血液疾病的转移。此次活动的近期目标中心致力于探索恒河猴子宫内基因转移的关键问题猴子模型，非常模拟人类。我们建议表演基因产前移植将为消除该病提供最佳机会与许多危及生命的先天性疾病相关的病理学，因为尽早传递纠正基因可能会防止器官或器官损伤以后的生活中无法接触到细胞。然而，在考虑申请之前对于人类胎儿来说，至关重要的是细胞趋向性、水平和相关动物模型中需要解决基因表达的持续时间和安全性问题比如猴子。我们的第一个目标是研究效率重组病毒载体系统将基因转移到胎儿恒河猴中猴子体内的心脏、肺和造血疾病。在目标 1，具体目标 1，我们将探讨转导的效率两个整合的病毒载体系统，自失活的 HIV-1 衍生慢病毒和腺相关病毒 (AAV)，使用全身和器官靶向接近。在这些研究中，组成型和细胞特异性将使用启动子，我们将把病毒载体构建体转移到胎儿猴在规定的胎龄和基于发育里程碑。在本目标的具体目标 2 中，我们将确定是否对转基因产品和/或载体产生免疫反应，并且确认器官结构和产后功能不会因此而改变我们的产前干预措施。我们的第二个目标侧重于提供为 NHLBI 资助的胎儿基因转移研究人员提供专业服务心脏、肺或血液疾病。在目标 2、具体目标 1 中，我们将为 NHLBI 资助的机构提供我们独特的灵长类动物专业知识、服务和资源希望评估病毒和非病毒基因转移的研究人员猴子的策略。为了有效地提供这些服务，该目标的具体目标 2 包括行政/科学计划监督、科学咨询委员会以及 NHLBI 资助的外展工作调查人员。我们建议通过建立胎儿中心猴子基因转移治疗心脏、肺和血液疾病，我们将能够探索基因转移策略出现时的效率，充分研究基因转移对胎儿、婴儿和婴儿的潜在影响母亲，并显着推进未来人类的基因治疗领域应用。