Cone Rescue in Retinitis Pigmentosa

项目总结/摘要 在北美失明的主要原因是遗传性视网膜变性和视网膜炎 色素沉着症（RP）是主要病因。RP是一组遗传性疾病，其特征在于 夜盲症的发病，周边视野的早期丧失，最终 丧失中央视觉。RP的常染色体显性形式的最常见形式是由 视紫红质中的Pro23 His突变导致视网膜变性-即P23 H 视网膜病变我们建立了P23 H视网膜病变的小型猪模型， 研究预防或延迟视力丧失发作的治疗方案。 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，基因和药物治疗。Leber's的基因转移 先天性黑蒙（LCA）是RP患者的一个小子集， 保证也就是说，其他形式的RP的基因治疗面临着几个挑战，包括 与这种疾病相关的各种突变。基于细胞的杆移植 来自许多来源的光感受器试图逆转RP的进展。 虽然RP的早期阶段是以中期开始的杆变性为标志， 周边视网膜，只有在疾病的后期阶段时，视网膜变性 大多数患者发现他们自己 患有严重的视力障碍这也是公认的，在RP，锥生存取决于 在正常的杆上。我们初步观察到， 来自猪诱导的多能干细胞（iPSC），注射到我们的视网膜下， P23 H视网膜病变的猪模型将在形态和功能上拯救该区域中的视锥 中央（类似于人的黄斑）。我们将证实这一观察，探索 视杆细胞源性视锥细胞活力因子（RdCVF）和 进一步研究了模型中锥损失的机理。我们的研究有可能 为了防止大多数RP患者发生功能性失明，不仅 P23 H突变的人。

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.