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

总结 该项目的目标是开发一种基于细胞的治疗方法，作为一种持久的视网膜下移植，以造福患者 干性年龄相关性黄斑变性（AMD）我们最近发现了一种新的成人视网膜色素 上皮干细胞，RPESC，在人类RPE层，自我更新，并产生高纯度 RPE后代群体（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，包括极化细胞因子分泌、液体转运、细胞因子分泌和细胞因子分泌。 以及视杆细胞外节的吞噬作用，这对于感光细胞存活和视网膜健康至关重要。与联合 罗切斯特GMP工厂（USCGF），我们开发了一种稳健、可重现的cGMP生产工艺。 每个RPESC系使用在使用后将被丢弃的材料与捐赠的球体分离。 角膜收集。我们不缺乏起始材料，每年向美国眼科捐赠约10万个地球仪 通过CLIA认证的符合FDA的供体检测的银行。从单个供体分离的RPESC可以产生 仅2次传代后的5x 108个RPESC-RPE后代。RPESC-RPE产品制造简单， 生产多个主细胞库（MCB）的低成本使得HLA配型在 未来根据FDA的指导，我们生产了临床级MCB，并进行了临床前IND- 使研究表明有利的安全性，没有肿瘤检测或毒性报告。使用两 在不同的大鼠模型中，我们证明了长期植入到RPE层和显著的视力拯救。 皇家外科医学院（RCS）大鼠，一种先前用于细胞移植IND使能研究的模型 关于AMD我们发现，在视网膜下移植成人RPESC衍生的RPE在中期阶段， 分化增加RCS大鼠的视力拯救，而早期或晚期细胞显著减少 灵验。我们对该有效阶段的研究已经能够鉴定候选效价标志物。的 研究者发起的再生医学创新项目（RMIP）的目标RFA-HL-18-030 应用于：1.与RM Innovation合作推出RPESC-RPE细胞产品的高级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， 解决移植的细胞功能以及体内整合和持久性，以及3.填写并提交IND 申请并准备I/IIa期临床试验。在完成每一项工作方面都取得了很大进展 这些目标，包括IND支持的安全性和有效性研究，这使得拟定的时间轴和 预算可行。拟议的临床试验，移植RPESC-RPE视网膜下作为一个悬浮液使用 建立了玻璃体视网膜手术技术，以尽量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小组 包括对干细胞产品和AMD患者有丰富经验的外科医生。我们的目标是改善日常生活， 大量AMD患者目前缺乏针对其进行性视力丧失的治疗选择。

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.