Development of stem cell-based therapies for limbal stem cell deficiency

开发基于干细胞的角膜缘干细胞缺陷疗法

• 批准号: 10393488
• 负责人: Sophie Deng
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393488
• 关键词: Allogenic; Animals; Applications Grants; Area; Autologous Transplantation; Biological Assay; Biological Markers; Biopsy; Blindness; Chemical Burns; Cicatrix; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cornea; Corneal Diseases; Corneal Opacity; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Eye; Eye diseases; Foundations; Functional disorder; Funding; Goals; Homeostasis; Imaging Techniques; In Vitro; Integration Host Factors; Keratoplasty; Knowledge; Laboratories; Laser Scanning Confocal Microscopy; Light; Measures; Methods; Outcome; Outcome Measure; Paper; Patients; Peer Review; Process; Production; Property; Protocols documentation; Publishing; Quality Control; Reporting; Residual state; Risk; Safety; Severities; Standardization; Stem Cell Development; Stem cell transplant; Surface; Techniques; Tissues; Transplantation; Transportation; Treatment Protocols; Treatment outcome; Vision; World Health Organization; Xenobiotics; assay development; base; clinical outcome assessment; clinical outcome measures; corneal epithelial stem cells; corneal epithelium; imaging modality; improved; in vivo; in vivo imaging; limbal; next generation; novel; safety and feasibility; stem cell function; stem cell population; stem cell therapy; stem cells; success; tool

Project summary/Abstract: Corneal blindness is the fourth leading cause of blindness in the world. Limbal stem cell deficiency (LSCD) is a blinding eye disorder due to the dysfunction or absence of corneal epithelial stem cells or limbal stem cells (LSCs), which maintain the normal homeostasis of the transparent corneal epithelium. LSCD, which is often undiagnosed and most challenging to treat is seen in many common eye diseases. The most desired treatment is transplantation of autologous LSCs in severe/total unilateral LSCD. The efficacy of transplantation of cultivated LSCs (cLSCs) has been reported in more than 37 studies since 1997. However, the cultivation protocol and the clinical outcome measures vary from study to study. Only three studies used GMP-compliant cLSCs. In addition, the success rate has not improved over the last two decades. To improve the efficacy and safety profile of the cLSCs, clinical trials using a standardized LSC cultivation and clinical protocol are necessary. To accomplish this goal, our laboratory has established a xenobiotic-free and feeder-free LSC culture method that can consistently produce cLSCs with properties that meet the criteria for high-level clinical success. Quantifiable in vitro parameters have been developed to characterize cLSCs and a newly developed in vivo imaging technique can be used to quantify LSC function in patients. In this proposal, we will establish these quantifiable in vitro parameters as in-process quality controls for the production of cLSCs and establish in vivo parameters as clinical outcome measures to objectively assess clinical outcomes. A pilot clinical study to evaluate the safety and efficacy of cLSCs produced under GMP condition will be conducted. Implementation of these in vitro and in vivo quantifiable parameters will make it possible to establish a standardized patient- specific stem cell therapy. The knowledge learned from the proposed study will form the foundation for the development of the next generation patient-specific limbal stem cell therapy.

项目概要/摘要： 角膜失明是世界上第四大失明原因。角膜缘干细胞缺乏症 (LSCD) 是 由于角膜上皮干细胞或角膜缘干细胞功能障碍或缺乏而导致的致盲眼病 （LSC），维持透明角膜上皮的正常稳态。 LSCD，通常是 许多常见眼部疾病均未确诊且治疗难度最大。最想要的治疗 是在严重/完全单侧 LSCD 中进行自体 LSC 移植。移植的功效 自 1997 年以来，已有超过 37 项研究报道了培养的 LSC（cLSC）。然而，培养 方案和临床结果测量因研究而异。只有三项研究使用了符合 GMP 的标准 cLSC。此外，近二十年来，成功率并没有提高。为了提高功效和 cLSC 的安全性、使用标准化 LSC 培养的临床试验和临床方案 必要的。为了实现这一目标，我们的实验室建立了不含外源物质和无饲养层的LSC 能够持续生产具有符合高水平临床标准的特性的 cLSC 的培养方法 成功。已开发出可量化的体外参数来表征 cLSC 和新开发的 体内成像技术可用于量化患者 LSC 功能。在本提案中，我们将建立 这些可量化的体外参数作为 cLSC 生产的过程质量控制，并建立 体内参数作为临床结果测量，以客观评估临床结果。试点临床研究 将评估在 GMP 条件下生产的 cLSC 的安全性和有效性。执行 这些体外和体内可量化参数将使建立标准化的患者成为可能 特定的干细胞疗法。从拟议研究中学到的知识将构成后续研究的基础 开发下一代患者特异性角膜缘干细胞疗法。