Cone Rescue in Retinitis Pigmentosa

视网膜色素变性的视锥细胞救援

• 批准号: 9762908
• 负责人: DOUGLAS Chase DEAN
• 金额: $ 60.7万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762908
• 关键词: ARHGEF5 gene; Adult; Animal Model; Area; Binding; Birth; Blindness; Cell Differentiation process; Cell Transplantation; Cell Transplants; Cells; Color Visions; Cone; Disabled Persons; Disease; Electrophysiology (science); Endoplasmic Reticulum; Evaluation; Face; Family member; Family suidae; Gene Transfer; Genes; Glucose; Hereditary Disease; Inherited; Label; Leber' s amaurosis; Light; Mitochondria; Modeling; Molecular Conformation; Morphology; Mus; Mutation; Neuroprotective Agents; Night Blindness; North America; Opsin; Patients; Peripheral; Pharmacotherapy; Population; Prevention; Process; Reading; Resolution; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinal Pigments; Retinitis Pigmentosa; Rhodopsin; Rod Outer Segments; Series; Source; Starvation; Stem cell transplant; Structure; Symptoms; TXN gene; Therapeutic; Time; Transplantation; Vertebrate Photoreceptors; Vision; Visual; Visual Fields; base; fetal; gene therapy; glucose transport; glucose uptake; hereditary blindness; in vivo; induced pluripotent stem cell; macula; man; mutant; neuroprotection; overexpression; preservation; prevent; restoration; retinal rods; sensor; synergism

Project Summary/Abstract A major cause of blindness in North America is hereditary retinal degeneration and Retinitis Pigmentosa (RP) is the leading cause. RP is a group of inherited diseases characterized by the onset of night blindness, the early loss of the peripheral visual field, and ultimately the loss of central vision. The most common form of autosomal dominant form of RP is caused by a Pro23His mutation in rhodopsin that results in retinal degeneration – i.e. P23H retinopathy. We have created and characterized a miniature pig model of P23H retinopathy to investigate therapeutic options to prevent or delay the onset of visual loss. Multiple therapeutic approaches have been or are being considered to prevent/delay the progression of RP, including cell-based, gene and drug therapies. Gene transfer in Leber's Congenital Amaurosis (LCA), a small subset of RP patients, shows very strong therapeutic promise. That said, gene therapy for other forms of RP faces several challenges including the wide variety of mutations associated with the disease. Cell–based transplantation of rod photoreceptors derived from a number of sources seeks to reverse the progression of RP. Although the early stage of RP is marked by the onset of rod degeneration in mid- peripheral retina, only in the late stages of the disease when retinal degeneration approaches the macula and cone degeneration ensues do most patients find themselves with a severe visual handicap. It also is well established that in RP, cone survival depends on normal rods. We have preliminarily observed that transplanted rod photoreceptors derived from pig induced Pluripotent Stem Cells (iPSCs) injected beneath the retina in our pig model of P23H retinopathy will rescue cones morphologically and functionally in the area centralis (analogous to the macula in man). We will confirm this observation, explore the synergistic effect of neuroprotection with rod derived cone viability factor (RdCVF) and further investigate the mechanism of cone loss in our model. Our studies have the potential to prevent the onset of functional blindness in the majority of patients with RP, not only those with the P23H mutation.

项目概要/摘要 北美失明的主要原因是遗传性视网膜变性和视网膜炎 色素变性 (RP) 是主要原因。 RP是一组遗传性疾病，其特征是 夜盲症的发作、周边视野的早期丧失，以及最终 中央视力丧失。 RP 最常见的常染色体显性遗传形式是由 视紫红质中的 Pro23His 突变导致视网膜变性，即 P23H 视网膜病变。我们创建并表征了 P23H 视网膜病变小型猪模型 研究预防或延缓视力丧失发生的治疗方案。 已经或正在考虑多种治疗方法来预防/延迟 RP 的进展，包括基于细胞的、基因和药物疗法。莱伯氏症的基因转移 先天性黑蒙（LCA）是 RP 患者的一小部分，显示出非常强大的治疗作用 承诺。也就是说，其他形式的 RP 的基因治疗面临着一些挑战，包括 与该疾病相关的多种突变。杆细胞移植 来自多种来源的光感受器试图逆转 RP 的进展。 尽管 RP 的早期阶段以视杆细胞中期开始退化为标志。 周边视网膜，仅在疾病晚期视网膜变性时 大多数患者发现自己接近黄斑和视锥细胞变性 患有严重的视力障碍。众所周知，在 RP 中，视锥细胞的生存取决于 在普通杆上。我们初步观察到移植的视杆细胞 源自猪的诱导多能干细胞（iPSC），注射到我们的视网膜下方 P23H 视网膜病变猪模型将从形态和功能上拯救该区域的视锥细胞 中央（类似于人类的黄斑）。我们将证实这一观察，探索 神经保护与视杆细胞衍生视锥细胞活力因子 (RdCVF) 和 进一步研究我们模型中锥体损失的机制。我们的研究有潜力 预防大多数 RP 患者出现功能性失明，不仅 那些有 P23H 突变的人。