Placental-specific therapy for fetal growth restriction

针对胎儿生长受限的胎盘特异性治疗

• 批准号: 9518997
• 负责人: HELEN N JONES
• 金额: $ 32.37万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9518997
• 关键词: Address; Adult; Adult Children; Amniocentesis; Animal Model; Blood Circulation; Cardiovascular Diseases; Cavia; Cell Line; Cells; Choriocarcinoma; Chorionic Villi Sampling; Complex; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Disease; Fetal Growth; Fetal Growth Retardation; Fetus; Fostering; Gene Transfer; Genetic Transcription; Giant Cells; Goals; Health; Healthcare; Human; Hypertension; Hypoxia; Image; Impaired cognition; Impairment; In Vitro; Injections; Insulin-Like Growth Factor I; Knowledge; Lead; Life; Mediating; MicroRNAs; Mission; Modeling; Mouse Strains; Mus; Nutrient; Obesity; Operative Surgical Procedures; Organ; Pathology; Peptides; Perinatal mortality demographics; Placenta; Placental Insufficiency; Placentation; Plasmids; Polymers; Pre-Eclampsia; Pregnancy; Pregnant Women; Public Health; Research; Research Training; Risk; Second Pregnancy Trimester; Spontaneous abortion; Syncytiotrophoblast; System; Technology; Time; Tissues; Toxic effect; United States National Institutes of Health; Villous; Woman; base; cognitive development; design; effective therapy; gene therapy; high risk; improved; in vivo; innovation; mother nutrition; mouse model; nanoparticle; nanoparticle delivery; non-viral gene delivery; particle; perinatal morbidity; perinatal period; premature; prenatal therapy; targeted treatment; transgene expression; treatment strategy; trophoblast; tumor; uptake

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.

项目摘要 在美国，胎儿生长受限（FGR）占所有妊娠的5-10%，目前没有 治疗大多数病例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、有效和特异性的非侵入性胎盘基因转移， 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， 基于纳米颗粒的纳米颗粒可以被人合胞体摄取并导致转基因表达， 跟踪和靶向纳米颗粒的非胎盘注射的发展。这背后的基本原理 该提议的目的是，预期它将朝着用于治疗的特定递送机制迈出重要的一步， 胎盘，并扩大知识的物质是由合胞体的 胎盘 为了实现本申请的目标，候选人打算追求以下具体目标： 目的1：将纳米颗粒递送和转基因表达靶向胎盘合胞体滋养层。 我们假设肽结合和器官特异性microRNA的掺入将有助于胎盘 纳米颗粒摄取和减少脱靶转基因表达。我们将利用体外人体和体内 研究纳米颗粒摄取、评估转基因表达和解决任何脱靶的小鼠研究 分娩后进入母体循环的影响。 目的2：在预先存在的胎儿生长受限模型中进行胎盘治疗。我们假设 纳米颗粒介导的胎盘IGF-1治疗将纠正受损的胎盘发育和胎儿生长， 预先存在的胎儿生长受限的动物模型。我们将使用Enos-/-小鼠品系和豚鼠 产妇营养限制模型，以探讨胎儿发病后胎盘特异性治疗的效果 生长限制，因为这将是在人类怀孕的情况下，直到能够预测胎盘 发展不足。 胎盘靶向治疗剂的使用是高度创新的，挑战了目前的治疗模式。 胎儿生长受限的管理和超越成像，靶向和破坏的基因治疗， 不需要的细胞拟议的研究是重要的，因为胎盘靶向系统的发展， 允许优先的纳米颗粒从母体循环输送到合体滋养层是至关重要的， 推动这项技术向前发展。最终，这些能力和知识有可能导致 开发出第一种有效的胎儿生长受限治疗方法。