Evaluation of stem cell-derived retinal pigment epithelial cells for retinal dise

干细胞来源的视网膜色素上皮细胞对视网膜疾病的评价

• 批准号: 8215696
• 负责人: MARTHA NEURINGER
• 金额: $ 43.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215696
• 关键词: Address; Adult; Age; Age related macular degeneration; Aging; Allografting; Animal Model; Animals; Autologous Transplantation; Biologic Characteristic; Biological; Biological Assay; Blindness; Cell Line; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Characteristics; Chronic; Clinic; Data; Degenerative Disorder; Disease; Dose; Engineering; Evaluation; Eye; Family suidae; Goals; Graft Rejection; Human; Immune; Immune response; Immune system; Immunologist; Immunology; Immunosuppression; In Vitro; Inflammation; Knowledge; Left; Light; Macaca mulatta; Measures; Metabolic; Methods; Mitochondria; Modeling; Molecular; Monkeys; Nonexudative age-related macular degeneration; Nutritional Support; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Photoreceptors; Physicians; Pluripotent Stem Cells; Primates; Production; Protocols documentation; Rattus; Recycling; Research Project Grants; Resources; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Retreatment; Risk; Rodent; Rodent Model; Scientist; Source; Stem cells; Structure; Structure of retinal pigment epithelium; Therapeutic Intervention; Time; Translational Research; Translations; Transplantation; Vision; Visual; Xenograft procedure; absorption; cell type; clinical practice; clinically relevant; disorder of macula of retina; embryonic stem cell; experience; immunogenicity; in vivo; induced pluripotent stem cell; innovation; insight; macula; nervous system disorder; nonhuman primate; novel; oxidation; pluripotency; prevent; public health relevance; retina transplantation; retinal rods; senescence; somatic cell nuclear transfer; success

DESCRIPTION (provided by applicant): Degenerative diseases of the retina are cumulatively the most common causes of untreatable blindness. These conditions, which include age-related macular degeneration and retinitis pigmentosa, are characterized by progressive loss of cells in the outer retina. Stem cells hold great promise for treating these diseases by repopulating cells that have been lost. A cell type that will be central to the success of this strategy is the retinal pigment epithelium (RPE). Recent technological breakthroughs make possible for the first time the production of recipient-specific donor cells through reprogramming of pluripotency in adult cells and directed differentiation. However, it is not known how RPE cells produced by these and other methods compare with respect to key biological characteristics, including immunogenicity and mitochondrial senescence, when transplanted to the healthy or diseased retina. These issues are critical to the potential use of such cells for retinal disease therapy. The goal of this proposal is to study the functionality of RPE cells generated from experimentally induced pluripotent stem cells in vitro and after transplantation to the rodent or nonhuman primate retina, including their immunogenicity and their ability to rescue visual loss in a rodent model of retinal degeneration. The project will make innovative use of unique resources, including allograft and autograft stem-cell-derived rhesus monkey RPE cell lines and a naturally-occurring nonhuman primate model of macular disease. The proposal has three specific aims: 1) To generate rhesus macaque RPE cells from three sources of pluripotent stem cells--embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (SCNT- ESCs), and induced pluripotent stem (iPS) cells--and evaluate their function in arresting visual decline in the RCS retinal degeneration model. 2) To investigate the immunology of these RPE cell types transplanted as allograft or autografts into the retina of adult rhesus monkeys and after retreatment of the same eye or fellow eye. 3) To characterize the differences in immune response between young and senescent rhesus monkeys, including those with age-related maculopathy which parallels intermediate human AMD. This translational research project will provide information key to the success of cell therapy in the retina. It will provide insights as to the most appropriate cell source to repopulate lost retinal cells with the aim of preserving or restoring vision, and will generate novel data on the immune response to such therapeutic intervention and the best approach to avoid graft rejection. The proposal will address these issues in an animal model with an eye and immune system that most closely resembles that of humans and in a manner closely mirroring potential clinical practice. PUBLIC HEALTH RELEVANCE: Retinal degenerative diseases are cumulatively the most frequent causes of blindness in which cells typically in the outer retina (photoreceptors and retinal pigment epithelium) are lost. This proposal focuses on the potential for replacing one such cell type, the retinal pigment epithelium, which can be engineered from various stem cell sources. The ability of these cells to rescue vision will be investigated and we will elucidate the risks of immune rejection. These findings will be key to the safe translation of this therapy into clinic for the treatment of such conditions as age-related macular degeneration.

描述（由申请人提供）：视网膜退行性疾病是导致无法治愈的失明的最常见原因。这些疾病包括与年龄相关的黄斑变性和色素性视网膜炎，其特征是外视网膜细胞逐渐丧失。干细胞通过再生丢失的细胞来治疗这些疾病具有广阔的前景。对于该策略的成功至关重要的细胞类型是视网膜色素上皮（RPE）。最近的技术突破首次使通过成体细胞多能性重编程和定向分化生产受体特异性供体细胞成为可能。然而，尚不清楚通过这些方法和其他方法产生的 RPE 细胞在移植到健康或患病视网膜时的关键生物学特征（包括免疫原性和线粒体衰老）如何比较。这些问题对于此类细胞用于视网膜疾病治疗的潜在用途至关重要。该提案的目的是研究体外实验诱导的多能干细胞产生的 RPE 细胞以及移植到啮齿动物或非人灵长类动物视网膜后的功能，包括其免疫原性以及在啮齿动物视网膜变性模型中挽救视力丧失的能力。该项目将创新地利用独特的资源，包括同种异体移植和自体移植干细胞衍生的恒河猴RPE细胞系以及天然存在的非人类灵长类黄斑疾病模型。该提案有三个具体目标：1）从三种来源的多能干细胞——胚胎干细胞（ESC）、体细胞核移植衍生的ESC（SCNT-ESC）和诱导多能干（iPS）细胞中产生恒河猴RPE细胞，并评估它们在RCS视网膜变性模型中阻止视力下降的功能。 2) 研究作为同种异体移植物或自体移植物移植到成年恒河猴视网膜中以及在同一只眼睛或对侧眼睛重新治疗后的这些RPE细胞类型的免疫学。 3) 表征年轻恒河猴和衰老恒河猴之间免疫反应的差异，包括那些患有与中间人类 AMD 相似的年龄相关性黄斑病的恒河猴。该转化研究项目将提供视网膜细胞疗法成功的关键信息。它将提供有关最合适的细胞来源的见解，以重新填充丢失的视网膜细胞，以保留或恢复视力，并将生成有关此类治疗干预的免疫反应的新数据以及避免移植排斥的最佳方法。该提案将在具有与人类最相似的眼睛和免疫系统的动物模型中解决这些问题，并以密切反映潜在临床实践的方式。 公共健康相关性：视网膜退行性疾病是导致失明的最常见原因，其中通常位于视网膜外层的细胞（光感受器和视网膜色素上皮）丢失。该提案的重点是替代一种这样的细胞类型——视网膜色素上皮细胞的潜力，这种细胞类型可以由各种干细胞来源改造而成。我们将研究这些细胞拯救视力的能力，并阐明免疫排斥的风险。这些发现对于将这种疗法安全地转化为临床治疗年龄相关性黄斑变性等疾病至关重要。