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

RPESC 衍生的 RPE 移植治疗非渗出性年龄相关性黄斑变性的 1/2a 期临床试验

• 批准号: 10487569
• 负责人: Jeffrey H Stern
• 金额: $ 63.84万
• 依托单位: REGENERATIVE RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487569
• 关键词: Adult; Age related macular degeneration; Amendment; Animal Model; Atrophic; Blindness; Caring; Cell Differentiation process; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Collection; Communication; Conduct Clinical Trials; Consent; Consent Forms; Cyclic GMP; Data; Data Collection; Elderly; Engraftment; Enrollment; Ensure; Eye; Genotype; Grant; Institutes; Institutional Review Boards; Interruption; Intervention; Investigation; Maintenance; Manuals; Manuscripts; Measures; Medical; Michigan; Modeling; Modification; Monitor; Nature; Nonexudative age-related macular degeneration; Outcome; Outcome Assessment; Pamphlets; Participant; Pathogenesis; Patient Recruitments; Patients; Phase; Phenotype; Pluripotent Stem Cells; Procedures; Protocols documentation; Rattus; Regenerative Medicine; Replacement Therapy; Reporting; Research Personnel; Retina; Review Committee; Risk; Safety; Site; Source; Specialist; Stem Cell Research; Stem cell transplant; Structure of retinal pigment epithelium; Supporting Cell; Surgeon; Time; Tissues; Translating; Translations; Transplantation; United States National Institutes of Health; Universities; Vision; Work; adult stem cell; aging population; base; catalyst; clinical research site; college; data management; design; early phase clinical trial; effective therapy; epithelial stem cell; experience; experimental study; eye center; improved; nerve stem cell; novel therapeutics; operation; post intervention; pre-clinical; preservation; progenitor; programs; quality assurance; recruit; repaired; retina transplantation; retinal progenitor cell; sound; stem cell biology; stem cells; transcriptome; transcriptomics; trial design; tumor; tumor growth

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.

项目摘要/摘要 老年性黄斑变性(AMD)是我国老龄化人口失明的主要原因之一。AMD的早期发病机制 涉及视网膜色素上皮(RPE)萎缩，并伴有视网膜功能和视力的丧失。虽然 渗出型(湿性)AMD有治疗方法，但更常见的非AMD没有有效的治疗方法。 渗出性(干性)AMD形式。多能干细胞(PSC)来源的RPE(PSC-RPE)移植显示出 AMD的早期临床试验。然而，由于PSC的高度增殖和可塑性，广泛分化为 移植前需要RPE，以避免肿瘤生长和PSC来源固有的基因不稳定性。我们 发现了一种具有有限增殖和谱系潜力的成人RPE干细胞(RPESC)。RPESC派生的RPE(RPESC- RPE)不会形成肿瘤，能够在祖细胞阶段移植分化较低的RPE。我们发现 移植的RPE祖细胞比高分化的后代更有效地挽救了皇家的视力 外科医学院大鼠AMD模型。RPESC-RPE分化4周，进入中间RPE祖细胞阶段 比分化8周的细胞更有效地挽救视力进入成熟的RPE表型。这一点改进了 疗效和缺乏致瘤性为拟议的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 经验丰富的临床试验团队已经在密歇根大学凯洛格眼科中心(KEC)和 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，他将招募， 实施干预，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，一名资深KEC视网膜专家将担任现场医疗监测员。一家诊所 在早期眼科试验中经验丰富的Triist将提供监管、设计和统计支持。这个 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，提供科学 以及拟议试验的临床指导。在NSCI产生的单细胞转录分析将与 临床结果，这将有助于认识到需要改进细胞产品特性和效力测量 一般在再生医学中。 我们建议将强大的干细胞生物学项目与一支经验丰富的眼科治疗团队结合起来。 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 移植治疗干性AMD结果将与产品认同度和效力测量相关联 单细胞水平。拟议工作的完成将提高对RM产品特性和 开发一种独特类型的成人干细胞来取代RPE，使干性AMD患者受益。