Center for Fetal Money Gene Transfer for HLB Diseases

描述(由申请人提供)： 这项建议的目的是建立一个胎儿猴子基因研究中心 心脏、肺脏和血液疾病的转院。这样做的直接目标是 中心是探索恒河猴宫内基因转移的关键问题 猴子模型，它非常接近于模拟人类。我们提出了执行基因 产前转让将为消除 与许多危及生命的先天性疾病有关的病理学，因为 及早传递纠正基因可能会防止器官或 在生命后期无法接触到的细胞。然而，在考虑申请之前 对于人类胎儿来说，重要的是细胞的嗜性、水平和 基因表达的持续时间和安全性在相关动物模型中得到解决 比如猴子。我们的第一个目标是调查 重组病毒载体系统在胚胎猕猴基因转移中的应用 猴子在体内用于心脏、肺和造血系统的疾病。在……里面 目标1，具体目标1，我们将探索转导效率 两个整合的病毒载体系统，自灭活HIV-1衍生 慢病毒和腺相关病毒(AAV)，使用全身和器官靶向 接近了。在这些研究中，构成和细胞特异性 将使用启动子，我们将把病毒载体的构建转移到 在确定的胎龄和基于发育的胚胎猴子 里程碑。在这一目标的具体目标2中，我们将确定 对转基因产品和/或载体产生免疫反应，以及 确认器官结构和出生后功能没有因此而改变 我们的产前干预措施。我们的第二个目标是提供 为NHLBI资助的胎儿基因转移研究人员提供专门服务 心脏、肺或血液疾病。在目标2，具体目标1中，我们将 将我们独特的灵长类专业知识、服务和资源提供给NHLBI资助 希望评估他们的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包括一项行政/科学计划 监督、科学咨询委员会和为NHLBI资助的外联工作 调查人员。我们建议通过建立胎儿研究中心 猴子的心肺和血液疾病的基因转移我们将能够 充分探索基因转移策略出现时的效率 研究基因转移对胎儿、婴儿和 母亲，并极大地推进了未来人类的基因治疗领域 申请。

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.