Novel Cell Free Therapy for Glaucoma

青光眼的新型无细胞疗法

基本信息

批准号：
10076404
负责人：
STEVEN ROTH
金额：
$ 3.24万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10076404
关键词：
Adverse effects Axon Biological Blindness Caliber Cell Death Cell Therapy Cell Transplantation Cell physiology Cells Clinical Clinical Research Data Analyses Data Collection Development Disease Engineering Ensure Exposure to Funding Glaucoma Goals Inflammatory Knowledge Medical Modification Operative Surgical Procedures Patients Physiologic Intraocular Pressure Precision therapeutics Reporting Research Research Design Retina Retinal Diseases Retinal Ganglion Cells Review Literature Route Schools Scientist Site Specificity Students Testing Therapeutic Uses Time Training Vision Visual Writing axon growth base clinical application clinical translation cost efficient design dosage excitotoxicity experience experimental study extracellular vesicles functional loss improved innovation interest intravitreal injection nanoparticle neuroprotection novel novel therapeutics prevent stem cells targeted delivery undergraduate student

项目摘要

A principal unmet need in glaucoma is that medical or surgical intraocular pressure reduction is the only clinically-approved treatment. But vision cannot be restored because retinal ganglion cell (RGC) loss is irre- versible. Knowledge gaps to improved therapy include how to achieve neuroprotection, i.e., preventing RGCs from dying, or, to use cell-based therapy to re-grow or replace. Administration route, dosage, and adverse effects limit clinical application of neuroprotection and cell transplantation. Studying a new treatment using extracellular vesicles (EVs), biologically-active 50-150 nm diameter nanoparticles derived from stem cells, the proposal fills a gap and urgent need in the development of new treatments to prevent RGC death and vision loss for glaucoma patients. EVs represent a potential clinically applicable means to prevent RGC, axonal, and visual functional loss and decreasing the excitotoxic and inflammatory component of glaucoma. Our central hypothesis is that EVs can be designed and optimized to specifically target RGCs as a basis for precision treatment of glaucoma and, ultimately, other retinal diseases. We propose to test engineered EVs as a novel cell-free means to specifically target neuroprotection to RGCs and to fill the knowledge gaps that presently prevent clinical translation of EVs for retinal disease. Our specific aims are Aim 1: Determine the time course and factors regulating the distribution of EVs in the vitreous and retina, and optimize EV delivery to retina. Aim 2: Develop and optimize novel engineered EVs to specifically target RGCs. Successful com- pletion of Aim 1 will optimize delivery of EVs to the retina following intravitreal injection. Aim 2 will guide administration of EVs to produce innovative, specific, targeted delivery into RGCs, allowing specificity for treatment at the major pathophysiological site of glaucoma. Fulfillment of these objectives will set the stage to develop glaucoma therapeutics using EVs by optimizing administration, and by specific RGC-targeted EVs. The study offers promise to save sight via development of safe, effective, and cost-efficient therapy to restore or prevent loss of sight in patients with glaucoma. This contribution is expected to be significant because these studies will provide a basis to develop EVs as a therapy for glaucoma, either primarily restoring RGC function and axonal growth, or optimizing existing therapies such as RGC transplants. Innovative features are cell- free therapy of glaucoma, novel targeted EVs for specific RGC action, and novel delivery materials for EVs. The supplement for Diversity proposes to train an undergraduate student in data collection and analysis, reviewing literature critically, designing experiments, and writing research reports. The student will be involved with the project in the summer and during the school year. The goal is to use this experience to increase the interest of the student in clinical research and ultimately to assist in ensuring more opportunities for diversifica- tion of the clinician scientific workforce.

青光眼的一个主要未满足的需求是药物或手术降低眼压是唯一的方法临床批准的治疗。但视力无法恢复，因为视网膜神经节细胞（RGC）的损失是不可预测的。易懂的。改进治疗的知识差距包括如何实现神经保护，即预防 RGC 免于死亡，或者使用基于细胞的疗法来重新生长或替换。给药途径、剂量及不良反应效应限制了神经保护和细胞移植的临床应用。研究一种新的治疗方法细胞外囊泡 (EV)，源自干细胞的具有生物活性的 50-150 nm 直径纳米颗粒，该提案填补了开发新疗法以预防 RGC 死亡和视力的空白和迫切需求青光眼患者的损失。 EVs 代表了一种潜在的临床适用手段，可预防 RGC、轴突和视觉功能丧失并减少青光眼的兴奋毒性和炎症成分。我们的中央假设电动车可以被设计和优化以专门针对 RGC 作为精度的基础治疗青光眼，并最终治疗其他视网膜疾病。我们建议将工程电动汽车作为一种新颖的产品进行测试无细胞方法专门针对 RGC 进行神经保护，并填补目前的知识空白阻止 EV 治疗视网膜疾病的临床转化。我们的具体目标是目标 1：确定时间进程以及调节 EV 在玻璃体和视网膜中分布的因素，并优化 EV 输送视网膜。目标 2：开发和优化专门针对 RGC 的新型工程电动汽车。成功的com- Aim 1 的完成将优化玻璃体内注射后 EV 向视网膜的输送。目标2将指导管理 EV，以向 RGC 提供创新、具体、有针对性的交付，从而实现特异性针对青光眼主要病理生理部位的治疗。这些目标的实现将为通过优化给药和特定的 RGC 靶向 EV，使用 EV 开发青光眼疗法。该研究有望通过开发安全、有效且具有成本效益的疗法来恢复视力或预防青光眼患者失明。预计这一贡献将是巨大的，因为这些研究将为开发 EV 治疗青光眼提供基础，主要是恢复 RGC 功能和轴突生长，或优化现有疗法，例如 RGC 移植。创新功能是细胞- 青光眼的免费治疗、针对特定 RGC 作用的新型靶向 EV 以及用于 EV 的新型输送材料。多样性的补充建议对本科生进行数据收集和分析方面的培训，批判性地回顾文献、设计实验并撰写研究报告。学生将参与其中在夏季和学年期间进行该项目。目标是利用这一经验来提高学生对临床研究的兴趣，并最终帮助确保更多的多样化机会临床医生科学队伍的重刑。