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.

项目概要/摘要 基于粒子的胎儿治疗是解决结构性疾病引起的器官损伤的一种有前途的方法 通过产前成像，可以诊断结构性疾病，并且成像特征可以预测严重程度。 胎儿手术已证明可以改善（但不能治愈）结构性疾病，例如 先天性膈疝 (CDH) 导致肺部生长受损，而脊柱裂 (MMC) 则导致肺部生长受损 胎儿手术的挑战在于其复杂性和侵入性。 这些程序以及在怀孕早期应用这些技术的限制在大多数情况下，更早。 治疗可缩短器官损伤的持续时间并延长正常器官生长的持续时间 我们已经生成了纳米粒子（NP）以表观遗传疗法的形式进行的数据。 特定的 microRNA 改变各种下游靶点并改善 CDH 大鼠的肺部生长。 通过临床技术，可以在怀孕早期通过针安全地进行手术 胎儿死亡率非常低（羊膜穿刺术和胎儿输血），以提高我们在这些方面的成功率。 动物模型中，我们将设计颗粒用于两种递送模式：1) 全身/静脉 (IV) 以到达体内 器官（肺）和 2）羊膜内（IA）以到达与羊水接触的组织部位（例如 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）在人类胎儿血液中以改善静脉注射，然后我们将使用优化的颗粒来传递表观遗传。 改善 CDH 大鼠模型肺形态的治疗 在目标 2 中，我们将测试和改善颗粒行为。 以及在大鼠、羔羊和人类羊水中的稳定性，以改善 IA 输送。我们将使用携带表观遗传的颗粒。 治疗大鼠模型 CDH 的疗法 最后，在目标 3 中，着眼于转化，我们将测试 的分布。 向肺和其他组织进行 IV 或 IA 给药后，羔羊体内产生的颗粒该项目利用了 两位主要研究人员的协同专业知识（生物医学工程和胎儿治疗） 已经合作多年，成功完成我们的目标将建立广泛的原则。 对胎儿治疗的影响，将为改善先天性儿童的预后提供策略 我们的策略——旨在临床转化——可能会带来一种改变范式的“现成的”。 结构性疾病的治疗由于其简单性，可以在许多医院提供。