Stem Cell Therapy for Glaucoma

青光眼干细胞疗法

• 批准号: 9313648
• 负责人: MARKUS H. KUEHN
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313648
• 关键词: Affect; Aqueous Humor; Biological Models; Biopsy; Blindness; Caring; Cell Line; Cell Transplantation; Cells; Characteristics; Clinical; Clinical Management; Clinical Trials; Coculture Techniques; Data; Dermal; Development; Disease; Disease Management; Drops; Elderly; Ensure; Ethics; Extracellular Matrix; Eye; Eye Banks; Eye diseases; Eyedrops; Face; Familiarity; Fibroblasts; Functional disorder; Funding; Genetic; Glaucoma; Goals; Graft Rejection; Harvest; Head; Human; Immune; Injection of therapeutic agent; International; Iowa; Laboratories; Lead; Legal; Life; Medical; Medical Records; Methodology; Methods; Modality; Monitor; Mus; Mutation; Natural regeneration; Operative Surgical Procedures; Organ Culture Techniques; Pathogenicity; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Physiological; Population; Prevention approach; Primary Open Angle Glaucoma; Procedures; Regulation; Research; Research Personnel; Residencies; Resistance; Resources; Risk; Risk Factors; Safety; Sampling; Savings; Services; Site; Skin; Source; Specialist; Stem cells; Stress; Structure; System; Testing; Tissues; Trabecular meshwork structure; Transgenes; Transplantation; United States; Universities; Veterans; Vision; Visit; age effect; age related; anterior chamber; base; cell type; clinically relevant; compliance behavior; cost; expectation; experience; functional restoration; induced pluripotent stem cell; innovation; mouse model; myocilin; non-compliance; novel; novel strategies; novel therapeutic intervention; older patient; prevent; public health relevance; restoration; standard of care; stem cell biology; stem cell therapy; therapy development

DESCRIPTION : Primary open angle glaucoma (POAG) is the second leading cause of blindness in the United States. This disease is strongly age-related and affects approximately 1.9% of the US population 40 years or older and is highly prevalent in veterans. The development of elevated intraocular pressure (IOP) is closely associated with the development of glaucoma and results from increased resistance to aqueous humor outflow through the trabecular meshwork (TM). To date, there is no cure for glaucoma. Vision loss is permanent and while elevated IOP can be managed through medical or surgical means, it does not resolve permanently. Current medical treatment requires daily or twice daily application of one or more eye drops for the remainder of a patient's life. Despite the importance of maintaining a well-controlled IOP, patient compliance is poor, resulting in lack of IOP control and progressive vision loss. Elderly patients, in particuar, suffer from involuntary non-compliance due to the difficulty of applying the drops to their eyes. Lack of compliance is a major challenge in the clinical management of the disease and consequently the development of treatment modalities that lead to permanent, reliable IOP control is highly desirable. The overall goal of this project is to develop new approaches to restore healthy IOP in patients with glaucoma. Specifically we propose to evaluate whether replacement of damaged or lost trabecular meshwork (TM) cells with stem cell derived TM like cells can induce functional restoration following transplantation into glaucoma eyes. We hypothesize that replacement of lost or damaged TM cells with healthy cells can preserve or restore aqueous humor outflow facility, decrease IOP, and thus preserve vision. The source of these cells is, of course, crucial. A patient's native TM cells are difficult to obtain and may additionally be functionally compromised due to the effects of age-related stresses. We propose that the use of TM-like cells derived from induced pluripotent stem cell (iPSC-TM), which can be created from the patient's own dermal fibroblasts, obtained from a skin biopsy, offers the best solution to this challenge. In order to test our hypothesis we will induce iPSC to differentiate ito iPSC-TM and test them functionally in an ocular perfusion organ culture system. Human donor eyes will receive a transplantation of iPSC-TM and will be monitored for up to three weeks for integration of stem cells into the TM, changes in the eye's outflow capacity, and changes in the TM extracellular matrix. We will also test our hypothesis using a new mouse model of glaucoma which was recently developed by the P.I. and his collaborators. These mice, which develop elevated IOP due to a transgene expressing a pathogenic mutation myocilin, are uniquely suited for these studies because damage to the structure of their TM is mild even though TM cells become dysfunctional. This unique and novel approach could provide effective, permanent, vision saving treatment for veterans with POAG as well as other types of glaucoma, such as exfoliation glaucoma. Upon completion of these studies we expect to have obtained conclusive data to determine if TM regeneration using stem cell derived TM-like cells is an effective and safe approach that could be used to treat patients with glaucoma. We expect that the proposed study will point out novel treatment approaches for the prevention of vision loss in veterans who suffer from glaucoma that is difficult to manage or who face challenges preventing consistent use of IOP lowering medications.

描述 ： 原发性开角青光眼（POAG）是美国失明的第二主要原因。该疾病与年龄有关，大约影响40岁以上的美国人口的1.9％，并且在退伍军人中非常普遍。眼内压（IOP）的发展与青光眼的发展密切相关，以及通过小梁网（TM）对水性幽默流出的耐药性增加而产生的。 迄今为止，无法治愈青光眼。视力丧失是永久性的，虽然可以通过医学或外科手段来管理IOP升高，但它无法永久解决。当前的医疗需要每天或每天两次在患者的余生中使用一个或多个眼部滴。尽管重要的是保持良好的IOP控制，但患者的依从性很差，导致缺乏IOP控制和进行性视力丧失。由于难以将滴剂涂在眼睛上，因此在特定的患者中，患者患有非自愿性违规。缺乏依从性是该疾病临床管理的主要挑战，因此非常需要导致永久性，可靠的IOP控制的治疗方式的发展。 该项目的总体目标是开发新方法来恢复青光眼患者的健康IOP。具体而言，我们建议用干细胞衍生的TM（如细胞）替换受损或丢失的小梁网（TM）细胞是否可以在移植到青光眼眼中诱导功能恢复。我们假设用健康细胞替换丢失或受损的TM细胞可以保留或恢复幽默流出设施，减少IOP，从而保持视力。这些细胞的来源当然至关重要。患者的天然TM细胞很难获得，并且由于年龄相关的应力的影响，可能会在功能上损害。我们建议使用源自诱导的多能干细胞（IPSC-TM）的TM样细胞，这些细胞可以从患者自身的皮肤活检中获得的皮肤成纤维细胞产生，为这一挑战提供了最佳解决方案。 为了检验我们的假设，我们将诱导IPSC区分ITO IPSC-TM并在眼部灌注器官培养系统中进行功能。人类的供体眼将接受IPSC-TM的移植，并将监测长达三周的干细胞，以将干细胞整合到TM中，眼睛流出容量的变化以及TM细胞外基质的变化。我们还将使用P.I最近开发的新型青光眼小鼠模型来检验我们的假设。和他的合作者。这些小鼠由于表达致病性突变肌动蛋白的转基因而产生的IOP升高，非常适合这些研究，因为即使TM细胞的功能障碍，对其TM的结构的损害也是轻度的。 这种独特而新颖的方法可以为具有POAG的退伍军人以及其他类型的青光眼提供有效，永久的避免视觉疗法，例如去角色青光眼。完成这些研究后，我们期望获得结论性数据，以确定使用干细胞得出的TM样细胞的TM再生是否是一种有效且安全的方法，可用于治疗青光眼患者。我们预计，拟议的研究将指出一种预防患有青光眼的退伍军人视力丧失的新型治疗方法，这些退伍军人难以管理，或者面临挑战，以防止持续使用IOP降低药物。

项目成果

iPSCs-Based Therapy for Trabecular Meshwork.

基于 iPSC 的小梁网治疗。

• DOI: 10.1007/164_2023_671
• 发表时间: 2023
• 期刊: Handbook of experimental pharmacology
• 作者: Zhu,Wei;Zhang,Xiaoyan;Wu,Shen;Wang,Ningli;Kuehn,MarkusH
• 通讯作者: Kuehn,MarkusH

Improved magnetic delivery of cells to the trabecular meshwork in mice.

改善细胞向小鼠小梁网的磁性输送。

• DOI: 10.1016/j.exer.2023.109602
• 发表时间: 2023
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: BahraniFard,MReza;Chan,Jessica;SanchezRodriguez,Gabriela;Yonk,Marybeth;Kuturu,ShreyaR;Read,AThomas;Emelianov,StanislavY;Kuehn,MarkusH;Ethier,CRoss
• 通讯作者: Ethier,CRoss