Transplantation of Adult, Tissue-Specific RPE Stem Cells as Therapy for Non-exudative Age-Related Macular Degeneration AMD

摘要 该项目的目标是开发一种基于细胞的疗法，作为一种持久的视网膜下移植，使患者受益。 患有干性老年性黄斑变性(AMD)。我们最近发现了一种新的成人视网膜色素 人类RPE层中的上皮干细胞，即RPESC，可自我更新并产生高度纯净的 RPE子代种群(RPESC-RPE)。在与NEI研究人员的合作中，我们已经证明 RPESC-RPE概括了天然RPE的关键功能，包括极化的细胞因子分泌、液体运输 以及视杆外节的吞噬作用，这对感光细胞存活和视网膜健康至关重要。与美国的关系。 在罗切斯特GMP工厂(USCGF)的帮助下，我们开发了一种坚固、可重复的cGMP制造工艺。 每条RPESC线路都使用原本会被丢弃的材料与捐赠的地球仪隔离 收集眼角膜。每年向美国眼捐赠约10万个地球仪，起始材料并不短缺 接受CLIA认证、符合FDA标准的捐赠者测试的银行。从单个供体分离的RPESCs可以产生 5×108 RPESC-RPE子代仅传2代。RPESC-RPE产品制造简单， 生产多个主细胞库(MCB)的低成本使患者的HLA配型在 未来。在FDA的指导下，我们生产了临床级MCB，并进行了临床前试验。 使研究表明良好的安全概况，没有肿瘤检测或毒性报告。使用两个 不同的大鼠模型，我们展示了RPE层的长期植入和显著的视力挽救 皇家外科学院(RCS)大鼠，这是一种先前被验证用于细胞移植IND研究的模型 对于AMD。我们发现成人RPESC来源的RPE视网膜下移植在 分化增加了RCS大鼠的视觉挽救，而早期或晚期细胞显著减少 很有效。我们对这一有效阶段的研究使我们能够识别候选的效力标记。这个 该再生医学创新项目(RMIP)研究人员发起的目标-HL-18-030 应用范围：1.与RM Innovation合作，推进RPESC-RPE细胞产品的CMC 预期临床试验和RMAT应用的催化剂；2.完成正在进行的组织学研究， 解决移植细胞的功能以及体内整合和持久性，以及3.完成并提交IND 申请并为I/IIa期临床试验做准备。在完成每一项工作方面都取得了很大进展 这些目标，包括支持IND的安全性和有效性研究，这使得拟议的时间表和 预算可行。建议的RPESC-RPE视网膜下移植临床试验用于 成熟的玻璃体视网膜手术技术，以最大限度地减少视网膜切开术的大小和手术并发症。临床 密歇根大学凯洛格眼科中心和斯坦福大学拜尔斯眼科研究所的试验团队 包括有干细胞产品经验的外科医生和AMD患者。我们的目标是改善人们的日常生活 目前对进行性视力丧失缺乏治疗选择的大量AMD患者。

Summary The goal of this project is to develop a cell-based therapy as a durable sub-retinal transplant to benefit patients with dry age-related macular degeneration (AMD). We recently discovered a novel adult retinal pigment epithelial stem cell, the RPESC, in the human RPE layer that self-renews and produces highly pure populations of RPE progeny (RPESC-RPE). In collaboration with NEI researchers, we have shown that RPESC-RPE recapitulate key functions of native RPE, including polarized cytokine secretion, fluid transport and phagocytosis of rod outer segments, critical for photoreceptor cell survival and retinal health. With the U. Rochester GMP facility (USCGF), we have developed a robust, reproducible cGMP manufacturing process. Each RPESC line is isolated from donated globes using material that would otherwise be discarded after cornea collection. There is no shortage of starting material as c.100,000 globes/year are donated to US eye banks with CLIA-certified FDA-compliant donor testing. RPESCs isolated from a single donor can produce 5x108 RPESC-RPE progeny after only 2 passages. The RPESC-RPE product is simple to manufacture, and the low-cost to produce multiple master cell banks (MCBs) makes HLA matching to patients feasible in the future. Following FDA guidance, we have produced a clinical grade MCB and performed pre-clinical IND- enabling studies that indicate a favorable safety profile with no tumor detection or toxicity reported. Using two different rat models, we demonstrated long-term engraftment into the RPE layer and significant vision rescue in the Royal College of Surgeons (RCS) rat, a model previously validated for cell transplant IND-enabling studies for AMD. We found that subretinal transplantation of adult RPESC-derived RPE at an intermediate stage of differentiation increases vision rescue in the RCS rat, while earlier or later stage cells were significantly less efficacious. Our studies of this efficacious stage have enabled identification of candidate potency markers. The goals of this Regenerative Medicine Innovation Project (RMIP) Investigator-initiated RFA-HL-18-030 application are to: 1. Advance CMC for the RPESC-RPE cell product in collaboration with the RM Innovation catalyst in anticipation of clinical trial and RMAT application; 2. Complete ongoing histology studies that address transplanted cell function and integration and persistence in vivo, and 3. Complete and submit the IND application and prepare for a Phase I/IIa phase clinical trial. Much progress has been made to complete each of these aims, including IND-enabling safety and efficacy studies, which makes the proposed timeline and budget feasible. The proposed clinical trial to transplant RPESC-RPE subretinally as a suspension uses established vitreoretinal surgical techniques to minimize retinotomy size and surgical complications. Clinical trial teams at the University of Michigan Kellogg Eye Center and the Stanford University Byers Eye Institute include surgeons experienced with stem cell products and AMD patients. Our goal is to improve daily living for the large number of AMD patients who currently lack therapeutic options for their progressive vision loss.