Retinal disease models for translational photoreceptor replacement

用于平移感光器替代的视网膜疾病模型

• 批准号: 10477226
• 负责人: William A. Beltran
• 金额: $ 137.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477226
• 关键词: 3-Dimensional; Animal Model; Behavioral Assay; Biological; Blindness; Brain; CNS processing; Canis familiaris; Cell Count; Cell Differentiation process; Cell Survival; Cell Transplantation; Cells; Cessation of life; Clinical Trials; Disease; Disease model; Dog Diseases; Engraftment; Eye diseases; Foundations; Functional Magnetic Resonance Imaging; Future; Gene therapy trial; Generations; Genes; Goals; Homologous Gene; Human; Hydrogels; Immunosuppression; Impairment; Inherited; Injections; Knowledge; Label; Lead; Leber' s amaurosis; Measures; Mediating; Methods; Modeling; Mutation; Natural regeneration; Neural Retina; Orthologous Gene; Outcome; Outcome Measure; Pathologic; Pathology; Patients; Phase I/II Clinical Trial; Photoreceptors; Play; Pluripotent Stem Cells; Property; Psychophysics; RPE65 protein; Recovery of Function; Regenerative Medicine; Replacement Therapy; Reporter; Research; Research Personnel; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinal Pigments; Retinal gene therapy; Rod; Role; Safety; Site; Specific qualifier value; Structure; Structure of retinal pigment epithelium; System; Therapeutic; Transplantation; Vertebrate Photoreceptors; Vision; Visual; Visual Cortex; Visual Pathways; Xenograft procedure; base; behavior test; canine model; clinically relevant; cost effective; differentiation protocol; experimental analysis; gene therapy; human disease; human model; human pluripotent stem cell; improved; induced pluripotent stem cell; inherited retinal degeneration; multi-electrode arrays; nerve stem cell; photoreceptor degeneration; precursor cell; prevent; relating to nervous system; research facility; response; restoration; retina transplantation; safety study; scaffold; stem cell biology; stem cells; success; translational model; translational study; treatment response; 3-Dimensional; Animal Model; Behavioral Assay; Biological; Blindness; Brain; CNS processing; Canis familiaris; Cell Count; Cell Differentiation process; Cell Survival; Cell Transplantation; Cells; Cessation of life; Clinical Trials; Disease; Disease model; Dog Diseases; Engraftment; Eye diseases; Foundations; Functional Magnetic Resonance Imaging; Future; Gene therapy trial; Generations; Genes; Goals; Homologous Gene; Human; Hydrogels; Immunosuppression; Impairment; Inherited; Injections; Knowledge; Label; Lead; Leber' s amaurosis; Measures; Mediating; Methods; Modeling; Mutation; Natural regeneration; Neural Retina; Orthologous Gene; Outcome; Outcome Measure; Pathologic; Pathology; Patients; Phase I/II Clinical Trial; Photoreceptors; Play; Pluripotent Stem Cells; Property; Psychophysics; RPE65 protein; Recovery of Function; Regenerative Medicine; Replacement Therapy; Reporter; Research; Research Personnel; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinal Pigments; Retinal gene therapy; Rod; Role; Safety; Site; Specific qualifier value; Structure; Structure of retinal pigment epithelium; System; Therapeutic; Transplantation; Vertebrate Photoreceptors; Vision; Visual; Visual Cortex; Visual Pathways; Xenograft procedure; base; behavior test; canine model; clinically relevant; cost effective; differentiation protocol; experimental analysis; gene therapy; human disease; human model; human pluripotent stem cell; improved; induced pluripotent stem cell; inherited retinal degeneration; multi-electrode arrays; nerve stem cell; photoreceptor degeneration; precursor cell; prevent; relating to nervous system; research facility; response; restoration; retina transplantation; safety study; scaffold; stem cell biology; stem cells; success; translational model; translational study; treatment response

Diseases of the neural retina or retinal pigment epithelium (RPE) cause a substantial number of sight-impairing disorders, many of which lead to the degeneration and death of photoreceptor cells. A number of naturally occurring inherited retinal degeneration (RD) diseases have been identified that are true homologues of human diseases. Our research team has been instrumental in demonstrating that AAV-mediated gene therapy for the retina in disease models plays a critical role in the translational continuum by permitting a rapid, cost-effective, and clinically relevant assessment of therapeutic responses and long-term outcomes of retinal gene therapy. However, the success of prior gene therapy trials depended on the presence of viable, albeit diseased, target cells. In contrast, the substantial loss of target cells in advanced RD will require therapeutic strategies that permit regeneration or replacement of photoreceptor cells and restoration of neural connectivity. Models of human retinal diseases can provide the foundational knowledge needed for photoreceptor replacement therapies to improve visual function, as specified in the AGI RFA. We have assembled a team of investigators with expertise in neural progenitor and pluripotent stem cell biology, retinal cell differentiation, inherited retinal disease pathology and therapy, and functional analysis of experimental RD treatments. The investigators have the expertise to assess therapeutic responses and to develop appropriate outcome measures to evaluate safety and efficacy. We have a dedicated retinal disease research facility to assess models of human retinal disorders. Our goal is to develop models in which to investigate the replacement of photoreceptors under disease conditions. The models will be used to identify key parameters of cell transplantation, engraftment, and differentiation that will be critical for studies of disease-specific applications of regenerative medicine for the retina. Key properties to be studied are physical transplantation parameters, distribution of donor cells within the host retina, donor cell differentiation and survival, cell connectivity and functionality within the retina, connectivity to the visual pathways in the brain and CNS processing, and behavioral assays for vision. Transplantation parameters will be studied using xenografts derived from two well-characterized and readily available human pluripotent stem cell reporter lines that label cones and rods or only rods. Concurrently, we will develop a within-species system for photoreceptor replacement by producing equivalent iPSCs and cone/rod and rod-only iPSC reporter lines for replacement of retinal photoreceptor cells to recapitulate the engraftment that would occur in human clinical trials using human cells. Once developed, the photoreceptor precursor cell transplants will be analyzed for integration and functionality in disease models in which differentiation into new rod and cone visual cells can be evaluated.

神经视网膜或视网膜色素上皮（RPE）的疾病会引起大量视力障碍疾病，其中许多导致感光细胞的退化和死亡。已经确定了许多自然存在的遗传性视网膜变性（RD）疾病，它们是人类疾病的真正同源物。我们的研究团队一直在证明疾病模型中的视网膜介导的视网膜基因疗法在转化连续体中起着至关重要的作用，通过允许对视网膜基因治疗的治疗反应和长期结局进行快速，具有成本效益和临床相关的评估，在转化连续体中起着关键作用。然而，先前基因治疗试验的成功取决于存在可行的靶细胞，尽管患病了。相比之下，晚期RD中靶细胞的实质性损失将需要允许再生或替代感光细胞的治疗策略并恢复神经连通性。人类视网膜疾病的模型可以提供光感受器置换疗法所需的基础知识，以改善AGI RFA中指定的视觉功能。我们已经组建了一个研究人员，在神经祖细胞和多能干细胞生物学，视网膜细胞分化，遗传性视网膜病理学和治疗以及实验RD治疗的功能分析方面具有专业知识。研究人员具有评估治疗反应并制定适当的结果措施以评估安全性和有效性的专业知识。我们有专门的视网膜疾病研究机构来评估人类视网膜疾病的模型。 我们的目标是开发在疾病条件下研究光感受器的替代模型。这些模型将用于识别细胞移植，植入和分化的关键参数，这对于对视网膜再生医学的特异性应用至关重要。要研究的关键特性是物理移植参数，宿主视网膜内的供体细胞的分布，供体细胞分化和存活率，视网膜内的细胞连接性和功能，与大脑和CNS处理的视觉途径的连通性以及视觉的行为分析。将使用源自两个特征良好且易于获得的人类多能干细胞报告线的异种移植物来研究移植参数，这些干细胞记者线将锥和杆或仅标记杆标记。同时，我们将通过产生等效的IPSC和锥/杆和仅杆型IPSC报告基因替换视网膜光感受器细胞来概括植入植物，以替换在人类临床试验中，从而替换了视网膜光感受器细胞，从而开发一种用于替代感光体替代的物种系统。一旦开发，将分析感光体前体细胞移植，以便在疾病模型中进行整合和功能，在这些模型中，可以评估分化为新的棒和锥体视觉细胞的疾病模型。