Placental-specific therapy for fetal growth restriction

项目摘要 在美国，胎儿生长受限(FGR)会导致5%-10%的妊娠并发症，目前没有 治疗。这些病例中的大多数是由于胎盘功能不全，研究表明这些婴儿 成年后患肥胖症、糖尿病和心血管疾病的风险很高。长期目标是 建立安全、有效和特异的非侵入性胎盘基因转移以建立潜在的 胎儿生长受限的治疗策略。本申请的总体目标是开发一种聚合物- 基于纳米颗粒，可被人类合胞体摄取并导致转基因表达，并允许 跟踪和靶向非胎盘注射纳米颗粒的进展。这背后的理由是 建议是，预计将在建立治疗的具体提供机制方面迈出重要的一步 并拓宽关于胎盘合胞体吞噬物质的知识。 胎盘。 为了实现本申请的目标，应聘者打算追求以下具体目标： 目的1：将纳米粒子靶向胎盘合体滋养层细胞并进行转基因表达。 我们假设，多肽结合和器官特异的microRNAs的结合将有助于胎盘 纳米颗粒的摄取和减少非靶标的转基因表达。我们将利用体外的人和体内的 研究纳米颗粒摄取、评估转基因表达和解决任何脱靶问题的小鼠研究 分娩进入母体循环后的影响。 目的2：胎盘治疗先天胎儿生长受限模型。我们假设 纳米粒介导的胎盘IGF-1治疗将纠正受损的胎盘发育和胎儿生长 先天胎儿生长受限的动物模型。我们将使用eNOS-/-小鼠品系和一只豚鼠 母体营养限制模型探讨胎盘特异性治疗对胎儿发病的影响 在预测胎盘的能力之前，生长受限将是人类怀孕的情况 不足是发展起来的。 胎盘靶向疗法的使用是高度创新的，对当前的治疗范式具有挑战性 胎儿生长受限的处理和移动基因治疗超越成像、靶向和破坏 不需要的细胞。这项拟议的研究意义重大，因为开发一种胎盘靶向系统来 允许优先将纳米颗粒从母体循环输送到合体滋养层细胞是必不可少的 推动这项技术向前发展。归根结底，这些能力和知识有可能导致 开发首个治疗胎儿生长受限的有效方法。

Project Summary Fetal Growth Restriction (FGR) complicates 5-10% of all pregnancies in the U.S.A and currently has no treatment. The majority of these cases are due to placental insufficiency and studies indicate that these babies are at high risk of developing obesity, diabetes and cardiovascular disease in adulthood. The long-term goal is to establish safe, efficacious and specific non-invasive placental gene transfer in order to establish potential treatment strategies for fetal growth restriction. The overall objective of this application is to develop a polymer- based nanoparticle that can be taken up by the human syncytium and result in transgene expression and allow tracking and targeting developments for non-placental injection of the nanoparticle. The rationale behind this proposal is that it is expected to make significant steps toward a specific delivery mechanism for therapy in the placenta and to broaden the knowledge by which substances are endocytosed by the syncytium of the placenta. To accomplish the objective of this application the candidate intends to pursue the following specific aims: Aim 1: Targeting nanoparticle delivery and transgene expression to the placental syncytiotrophoblast. We hypothesize that peptide conjugation and the incorporation of organ-specific microRNAs will aid placental nanoparticle uptake and reduce off-target transgene expression. We will utilize in vitro human and in vivo murine studies to investigate nanoparticle uptake, assess transgene expression and address any off-target effects following delivery into the maternal circulation. Aim 2: Placental therapy in models of pre-existing fetal growth restriction. We hypothesize that nanoparticle-mediated placental IGF-1 therapy will rectify impaired placental development and fetal growth in animal models of pre-existing fetal growth restriction. We will use the Enos-/- mouse strain and a Guinea pig model of maternal nutrition restriction to investigate effects of placental-specific therapy after the onset of fetal growth restriction as would be the scenario in human pregnancy until the ability to predict placental insufficiency is developed. The use of placentally-targeted therapeutics are highly innovative, challenging current paradigms for the management of fetal growth restriction and moving gene therapy beyond imaging, targeting, and destruction of unwanted cells. The proposed research is significant because development of a placental targeting system to allow preferential nanoparticle delivery from the maternal circulation to the syncytiotrophoblast is essential to move this technology forward. Ultimately such capabilities and knowledge has the potential to lead to the development of the first effective treatment for Fetal Growth Restriction.