Novel Cell Free Therapy for Glaucoma

青光眼的新型无细胞疗法

• 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
• 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

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.

青光眼中未满足的主要需求是药物或手术眼内压降低是唯一的治疗方法。 临床批准的治疗。但视力不能恢复，因为视网膜神经节细胞（RGC）的损失是不可恢复的。 真实的改善治疗的知识差距包括如何实现神经保护，即，预防RGC 避免死亡，或者使用基于细胞的治疗来重新生长或替代。给药途径、剂量和不良反应 这些影响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），来源于干细胞的生物活性的50-150 nm直径的纳米颗粒， 该提案填补了一个空白，迫切需要开发新的治疗方法，以防止RGC死亡和视力 青光眼患者的损失。EV代表了预防RGC、轴突和神经节的潜在临床适用手段。 视觉功能丧失和减少青光眼的兴奋毒性和炎症成分。我们的中央 假设EV可以被设计和优化为特异性靶向RGC，作为精确度的基础 治疗青光眼，并最终治疗其他视网膜疾病。我们建议测试工程电动汽车作为一种新的 无细胞意味着特异性靶向RGC的神经保护，并填补了目前 防止EV临床转化为视网膜疾病。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递送， 视网膜。目标2：开发和优化新型工程EV以特异性靶向RGC。成功的com- Aim 1的加入将优化玻璃体内注射后EV向视网膜的递送。目标2将指导 给予EV以产生创新的、特异性的、靶向递送到RGC中，允许特异性地 治疗青光眼的主要病理生理部位。实现这些目标将为以下方面奠定基础： 通过优化给药和特异性RGC靶向EV，开发使用EV的青光眼治疗剂。 这项研究提供了通过开发安全，有效和具有成本效益的治疗方法来恢复视力的希望。 或预防青光眼患者的视力丧失。预计这一贡献将是巨大的，因为这些 研究将为开发EV作为青光眼治疗提供基础，主要恢复RGC功能 和轴突生长，或优化现有的治疗，如RGC移植。创新功能是细胞- 青光眼的免费治疗，用于特异性RGC作用的新型靶向EV，以及EV的新型递送材料。 多样性的补充建议在数据收集和分析方面培训本科生， 批判性地回顾文献，设计实验，撰写研究报告。学生将参与 在夏季和学年期间，我们的目标是利用这些经验来增加 学生对临床研究的兴趣，并最终协助确保多样化的更多机会， 临床医生科学劳动力。