Engineering of Polymeric Particles for Fetal Therapy

用于胎儿治疗的聚合物颗粒工程

• 批准号: 10586282
• 负责人: W. Mark Saltzman
• 金额: $ 43.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586282
• 关键词: Address; Amniocentesis; Amniotic Fluid; Animal Model; Animals; Behavior; Binding Proteins; Biomedical Engineering; Birth; Blood Transfusion; Characteristics; Chemistry; Child; Childhood; Clinical; Congenital diaphragmatic hernia; Cystic Fibrosis; Data; Diagnosis; Diaphragmatic Hernia; Disease; Early treatment; Effectiveness; Engineering; Environment; Epithelium; Exposure to; Eye; Fetal Diseases; Fetal Lung; Fetal Tissues; Fetal safety; Fetus; Genes; Genetic Diseases; Goals; Growth; Hematopoietic stem cells; Hemoglobinopathies; Hospitals; Human; Image; Impairment; Intervention; Intravenous; Learning; Liquid substance; Lung; Lung diseases; Medical; MicroRNAs; Modeling; Morbidity - disease rate; Morphology; Nature; Needles; Operative Surgical Procedures; Organ; Outcome; Performance; Polymers; Pre-Clinical Model; Pregnancy; Principal Investigator; Procedures; Proliferating; Proteins; Rattus; Rodent; Route; Safety; Severities; Site; Spinal Cord; Spinal Dysraphism; Structure of parenchyma of lung; Surface; Techniques; Testing; Therapeutic Agents; Time; Tissues; Translating; Translations; Work; biocompatible polymer; clinical translation; design; disease diagnosis; disease phenotype; effective therapy; epigenetic therapy; fetal; fetal blood; fetal medicine; fetus surgery; gene therapy; human fetus tissue; improved; improved outcome; in utero; intravenous administration; microRNA delivery; migration; minimally invasive; mortality; nanoparticle; nanoparticle delivery; organ growth; particle; prenatal; prenatal therapy; prevent; safety testing; stem cells; success; ultrasound; uptake

PROJECT SUMMARY/ABSTRACT Particle-based fetal therapy is a promising approach to address organ damage caused by structural diseases in utero. By prenatal imaging, structural diseases can be diagnosed and imaging features can predict the severity of outcome. Fetal surgery has demonstrated improved outcomes (but not cures) for structural diseases such as congenital diaphragmatic hernia (CDH), where lung growth is impaired and spina bifida (MMC) where the unprotected spinal cord is damaged. The challenges with fetal surgery are the complexity and invasive nature of these procedures and the limit to how early in pregnancy these techniques can be applied. In most cases, earlier treatment results in shortened duration of organ damage and longer duration of normal organ growth and development. We have generated data that nanoparticles (NPs) carrying epigenetic therapy in the form of specific microRNAs changes various downstream targets and improves the growth of lung in a rat of CDH. This approach can be delivered safely through a needle very early in pregnancy by clinical techniques that carry a very low rate of fetal demise (amniocentesis and fetal blood transfusion). To improve on our success in these animal models, we will engineer particles for two modes of delivery: 1) systemic/intravenous (IV) to reach internal organs (lung) and 2) intra-amniotic (IA) to reach tissues sites that are in contact with the amniotic fluid (such as the lung epithelial surface). In aim 1, we will test and improve particle behavior (stability and controlled protein binding) in human fetal blood to improve IV delivery. We will then use optimized particles to deliver epigenetic therapy to improve lung morphology in the rat model of CDH. In aim 2, we will test and improve particle behavior and stability in rat, lamb and human amniotic fluid to improve IA delivery. We will use particles carrying epigenetic therapy to treat a rat model CDH. Finally, with an eye on translation, in aim 3, we will test the distribution of particles in lamb after IV or IA administration to lung and other tissues. This project takes advantage of the synergistic expertise (biomedical engineering and fetal therapy) of the two principal investigators who have already worked together for several years. Successful completion of our aims will establish principles with broad implications for fetal therapy, would inform strategies to improve outcomes for children afflicted with congenital diseases. Our strategies—which aim for clinical translation—could lead to a paradigm-changing “off-the-shelf” therapy for structural diseases that, due to their simplicity, could be offered at many hospitals.

项目总结/摘要 基于粒子的胎儿治疗是一种很有前途的方法，以解决由结构性疾病引起的器官损伤， 子宫。通过产前影像学检查，可以诊断结构性疾病，影像学特征可以预测疾病的严重程度 的结果。胎儿手术已经证明改善了结构性疾病的结果（但不能治愈），如 先天性腹股沟疝（CDH），肺生长受损，脊柱裂（MMC）， 未受保护的脊髓受损。胎儿手术的挑战是复杂性和侵入性， 这些程序以及这些技术在怀孕早期可以应用的限制。在大多数情况下， 治疗导致器官损伤的持续时间缩短和正常器官生长的持续时间延长， 发展我们已经生成的数据表明，纳米颗粒（NPs）携带表观遗传疗法的形式， 特异性microRNA改变多种下游靶点并改善CDH大鼠肺的生长。这 通过临床技术，可以在怀孕早期通过针头安全地提供这种方法， 胎儿死亡率极低（胎盘穿刺术和胎儿输血）。为了提高我们在这些方面的成功， 在动物模型中，我们将设计用于两种递送模式的颗粒：1）全身/静脉内（IV）以到达内部 器官（肺）和2）羊膜内（IA）以到达与羊水接触的组织部位（例如 肺上皮表面）。在目标1中，我们将测试和改进颗粒行为（稳定性和受控蛋白质 结合）以改善IV递送。然后我们将使用优化的粒子将表观遗传 治疗以改善CDH大鼠模型中的肺形态。在aim 2中，我们将测试和改进粒子行为 以及在大鼠、羔羊和人羊水中的稳定性以改善IA递送。我们将使用携带表观遗传的粒子 治疗大鼠模型CDH的方法。最后，着眼于翻译，在aim 3中，我们将测试 IV或IA给药至肺和其他组织后，该项目利用了 两名主要研究者的协同专业知识（生物医学工程和胎儿治疗）， 已经共事好几年了成功地完成我们的目标将建立广泛的原则， 胎儿治疗的影响，将告知战略，以改善患有先天性心脏病的儿童的结果， 疾病我们的战略旨在临床翻译，可能会带来范式改变的“现成” 结构性疾病的治疗，由于其简单性，可以在许多医院提供。