Stem Cell Therapy for Glaucoma

产品说明： 原发性开角型青光眼（POAG）是美国第二大致盲原因。这种疾病与年龄密切相关，影响约1.9%的40岁或以上的美国人口，在退伍军人中非常普遍。眼内压（IOP）升高的发展与青光眼的发展密切相关，并且是由于对通过小梁网（TM）流出的房水的阻力增加所致。 青光眼的治疗方法有哪些？视力丧失是永久性的，虽然IOP升高可以通过医疗或手术手段进行管理，但它不会永久解决。目前的医学治疗需要在患者的余生中每天或每天两次施用一种或多种滴眼剂。尽管维持良好控制的IOP很重要，但患者依从性差，导致IOP控制不足和进行性视力丧失。特别是老年患者，由于难以将滴剂施用于他们的眼睛而遭受非自愿的不依从性。缺乏依从性是该疾病临床管理的一个主要挑战，因此非常需要开发能够永久、可靠地控制IOP的治疗方式。 该项目的总体目标是开发新的方法来恢复青光眼患者的健康IOP。具体而言，我们建议评估是否替换受损或丢失的小梁网（TM）细胞与干细胞衍生的TM样细胞可以诱导功能恢复移植到青光眼眼睛。我们假设用健康细胞替换丢失或受损的TM细胞可以保护或恢复房水流出功能，降低IOP，从而保护视力。当然，这些细胞的来源至关重要。患者的天然TM细胞难以获得，并且由于年龄相关的压力的影响，可能另外在功能上受到损害。我们建议使用来自诱导多能干细胞（iPSC-TM）的TM样细胞，该细胞可以从患者自己的皮肤成纤维细胞中产生，从皮肤活检中获得，为这一挑战提供了最佳解决方案。 为了验证我们的假设，我们将诱导iPSC分化为iPSC-TM，并在眼部灌注器官培养系统中测试它们的功能。人类供体眼睛将接受iPSC-TM移植，并将监测长达三周的干细胞整合到TM中，眼睛流出能力的变化以及TM细胞外基质的变化。我们还将使用P.I.最近开发的一种新的青光眼小鼠模型来测试我们的假设。和他的合作者。这些小鼠由于转基因表达致病性突变myocilin而导致IOP升高，因此特别适合这些研究，因为即使TM细胞功能失调，对TM结构的损伤也是轻微的。 这种独特而新颖的方法可以为患有POAG以及其他类型青光眼（如剥脱性青光眼）的退伍军人提供有效，永久，挽救视力的治疗。在完成这些研究后，我们希望获得结论性数据，以确定使用干细胞衍生的TM样细胞进行TM再生是否是一种有效和安全的方法，可用于治疗青光眼患者。我们预计，拟议的研究将指出新的治疗方法，用于预防患有青光眼的退伍军人的视力丧失，这些青光眼难以管理或面临阻止持续使用降眼压药物的挑战。

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.