Retinal disease models for translational photoreceptor replacement

神经视网膜或视网膜色素上皮（RPE）疾病引起大量视力损害疾病，其中许多疾病导致光感受器细胞变性和死亡。许多自然发生的遗传性视网膜变性（RD）疾病已被确定为人类疾病的真正同源物。我们的研究团队在证明疾病模型中aav介导的视网膜基因治疗在翻译连续体中起着关键作用方面发挥了重要作用，允许对视网膜基因治疗的治疗反应和长期结果进行快速、经济、临床相关的评估。然而，先前基因治疗试验的成功依赖于存活的靶细胞，尽管存在病变。相比之下，晚期RD中靶细胞的大量损失将需要允许再生或替换光感受器细胞和恢复神经连接的治疗策略。如AGI RFA所述，人类视网膜疾病模型可以为光感受器替代疗法改善视觉功能提供所需的基础知识。我们已经组建了一个研究团队，他们在神经祖细胞和多能干细胞生物学、视网膜细胞分化、遗传性视网膜疾病病理和治疗以及实验性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的专业知识，并制定适当的结果措施来评估安全性和有效性。我们有一个专门的视网膜疾病研究设施来评估人类视网膜疾病的模型。

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.