Phase1/2a Clinical Trial of RPESC-derived RPE Transplantation as Therapy for Non-exudative Age-related Macular Degeneration

项目总结/摘要 视网膜相关性黄斑变性（AMD）是我们老龄化人口中失明的主要原因。早期AMD发病机制 涉及视网膜色素上皮（RPE）的萎缩，伴随视网膜功能和视力的丧失。虽然 治疗可用于渗出性（湿性）AMD，有效的治疗是不可用于更常见的非- 渗出性（干性）AMD形式。多能干细胞（PSC）衍生的RPE（PSC-RPE）移植已经显示出用于治疗视网膜病变的前景。 早期临床试验中的AMD然而，由于PSC的高度增殖性和可塑性， 在移植前需要RPE以避免PSC来源固有的肿瘤生长和基因型不稳定性。我们 发现了一种具有有限增殖和谱系潜能的成人RPE干细胞（RPESC）。RPESC衍生的RPE（RPESC- RPE）不形成肿瘤，使得分化较低的RPE在祖细胞阶段能够移植。我们发现 在皇家的视力拯救中，移植的RPE祖细胞比高分化的后代更有效。 外科医生学院的AMD大鼠模型。RPESC-RPE分化4周进入中间RPE祖细胞阶段 比分化8周进入成熟RPE表型的细胞更有效地挽救视力。这种改进 有效性结合缺乏致瘤性为拟定的1/2a期临床试验提供了令人信服的理由， RPESC-RPE移植治疗干性AMD 密歇根大学凯洛格眼科中心（KEC）已组建了经验丰富的临床试验团队， 斯坦福大学。KEC团队包括一名在干细胞研究方面经验丰富的玻璃体视网膜外科医生， 进行干预，并管理参与者护理。另一位视网膜专家将指导干预后评估 在KEC临床研究中心，一名高级KEC视网膜专家将担任现场医疗监测员。临床 在早期眼科试验中经验丰富的试验员将提供法规、设计和统计支持。的 神经干细胞研究所（NSCI）和斯坦福大学拜尔斯眼科研究所将与KEC合作， 和临床指南。在NSCI生成的单细胞转录组学分析将与 临床结果，这将有助于提高细胞产品鉴别和效价测量的公认需求 在再生医学中的应用 我们建议联合收割机将干细胞生物学方面的强大项目与眼科领域经验丰富的团队结合起来， 临床试验良好的临床试验旨在产生可靠的结果，以评估RPESC-RPE祖细胞 干细胞移植治疗干性AMD。结果将与产品鉴别和效价测量相关， 单细胞水平。完成拟议工作将提高对RM产品表征的理解， 开发一种独特类型的成体干细胞来替代RPE，为干性AMD患者带来益处。

Project Summary/Abstract Age-related macular degeneration (AMD) is a major cause of blindness in our aging population. Early AMD pathogenesis involves atrophy of the retinal pigment epithelium (RPE) with accompanying loss of retinal function and vision. Although therapy is available for exudative (wet) AMD, an effective treatment is not available for the more common non- exudative (dry) AMD form. Pluripotent stem cell (PSC)-derived RPE (PSC-RPE) transplantation has shown promise for AMD in early clinical trials. Due to the highly proliferative and plastic nature of PSC, however, extensive differentiation to RPE is needed prior to transplantation to avoid tumor growth and genotype instability inherent to the PSC source. We discovered an adult RPE stem cell (RPESC) with restricted proliferative and lineage potential. RPESC-derived RPE (RPESC- RPE) do not form tumor enabling transplantation of less differentiated RPE at the progenitor stage. We found that transplanted RPE progenitor cells were more effective than highly differentiated progeny at vision rescue in the Royal College of Surgeons rat model of AMD. RPESC-RPE differentiated for 4 weeks into an intermediate RPE progenitor stage rescued vision more effectively than cells differentiated for 8 weeks into the mature RPE phenotype. This improved efficacy combined with lack of tumorgenicity provides compelling rationale for the proposed Phase 1/2a clinical trial of RPESC-RPE transplantation as therapy for dry AMD. Experienced clinical trial teams have been assembled at the University of Michigan Kellogg Eye Center (KEC) and Stanford University. The KEC team includes a vitreoretinal surgeon experienced in stem cell research who will recruit, perform interventions, and manage participant care. Another retinal specialist will direct post-intervention assessment at the KEC Clinical Research Center, and a senior KEC retinal specialist will serve as on-site medical monitor. A clinical trialist highly experienced in early phase ophthalmic trials will provide regulatory, design and statistical support. The Neural Stem Cell Institute (NSCI) and the Stanford University Byers Eye Institute will work with KEC to provide scientific and clinical guidance for the proposed trial. Single cell transcriptomic analyses generated at NSCI will be correlated with clinical outcomes, which will contribute to the recognized need for improved cell product identity and potency measures in regenerative medicine generally. We propose to combine a strong program in stem cell biology with an experienced team in the conduct of ophthalmic clinical trials Sound clinical trial conduct aims to produce reliable outcomes results to evaluate RPESC-RPE progenitor cell transplantation as therapy for dry AMD. Outcomes will be correlated with product identity and potency measures at the single cell level. Completion of the proposed work will improve understanding of RM product characterization and advance a unique type of adult stem cell to replace RPE for dry AMD patient benefit.