Phase I Study of Mesenchymal Stromal Cell Secretome for Promoting Corneal Regeneration

间充质基质细胞分泌组促进角膜再生的一期研究

• 批准号: 10487558
• 负责人: ALI R DJALILIAN
• 金额: $ 33.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487558
• 关键词: Address; Adult; Affect; Allogenic; Anti-Inflammatory Agents; Autoimmune Diseases; Blindness; Bone Marrow; Chemical Injury; Chronic; Cicatrix; Clinic; Clinical; Clinical Research; Clinical Trials; Cornea; Corneal Diseases; Corneal Opacity; Data; Development; Diabetes Mellitus; Dose; Drops; Enrollment; Eye; Eyedrops; Fatty acid glycerol esters; Fibrosis; Freezing; Future; Illinois; Immune; Immune System Diseases; Impairment; Individual; Inflammation; Laboratories; Laboratory Study; Lead; Limbus Corneae; Maintenance; Mediating; Mesenchymal; Nerve; Outcome Measure; Pathologic; Patients; Perforation; Pharmacy facility; Phase; Play; Pre-Clinical Model; Production; Property; Protocols documentation; Readiness; Regenerative Medicine; Regulation; Research Personnel; Risk; Role; Safety; Stromal Cells; Supportive care; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Treatment Efficacy; Ulcer; Universities; Vial device; Visit; adult stem cell; base; clinical application; corneal epithelial wound healing; corneal epithelium; corneal regeneration; corneal repair; cryogenics; epithelial stem cell; epithelial wound; follow-up; human disease; immunoregulation; innovation; limbal; melting; mesenchymal stromal cell; neovascularization; novel; open label; patient subsets; phase 1 study; pre-clinical; preclinical study; prevent; primary outcome; product development; regenerative; response; safety study; safety testing; secondary outcome; severe injury; standard of care; stem; stem cell therapy; stem cells; tissue regeneration; tissue repair; treatment duration; treatment strategy; wound closure; wound healing

Abstract Non-healing corneal wounds are a challenging condition with limited treatment options that can lead to significant loss of vision. They can occur in many settings such as: (1) chronic loss of nerves such as diabetes (2) following infectious/immune ulcers, and (3) corneas with insufficient stem cells (e.g. after severe injuries, or auto-immune diseases). The currently available therapies are limited by the inability to significantly promote tissue repair and prevent pathologic responses including ulcerations/melts and scarring/fibrosis. As a result, not only is there significant delay in epithelial wound closure but also there is significant scarring, and risk of perforation. The significant regenerative, immunomodulatory and anti-scarring effects of mesenchymal stromal cells (MSCs) have been shown in many studies, some of which were conducted by our team. Numerous studies have shown that the therapeutic effects of MSCs are mainly mediated through their secreted factors. We have optimized a treatment strategy based on MSC derived factors (secretome) to accelerate corneal wound healing and limit unnecessary inflammation and secondary scarring in pre-clinical models. This proposed clinical trial will address the gap between these extensive laboratory studies with promising results and the clinical application of MSC secreted factors. We propose a new treatment utilizing MSC secretome to use as an eye drop to accelerate corneal wound healing in patients with non-healing corneal wounds. Clinical grade MSC will be grown in the University of Illinois Stem Cell Laboratory using established protocols in line with the FDA requirements. Secretome will be collected and frozen in vials which will be later thawed individually dispensed to the patients by the pharmacy on a weekly basis. MSC Secretome will be applied as one drop four times per day in the affected eye in addition to the standard of care supportive therapy, as instructed by the investigator. The phase I safety study will involve 12 patients that will be treated with 2, 4, or 8 weeks of secretome to assess the safety and tolerated dose with weekly follow up visits. Following this, an additional group of 12 patients (different subsets of patients) will be enrolled and receive the maximum tolerable duration of treatment to further assess the safety and efficacy of the treatment with weekly follow up visits to serve as preliminary data for a possible future study. At the conclusion of these studies, we will gain valuable information regarding the safety of this treatment approach, as well as preliminary data about the efficacy in terms of wound healing. These will facilitate the development of novel stem cell based therapies for the management of visually disabling wound healing disorders of the cornea and potentially other tissues.

抽象的 不愈合的角膜伤口是一种具有挑战性的疾病，治疗选择有限，可以 导致视力严重丧失。它们可能发生在许多情况下，例如：(1) 慢性丧失 神经，如糖尿病 (2) 感染性/免疫性溃疡后，以及 (3) 角膜功能不全 干细胞（例如严重受伤或自身免疫性疾病后）。目前可用的疗法 由于无法显着促进组织修复和预防病理反应而受到限制 包括溃疡/融化和疤痕/纤维化。结果不仅造成了严重的延误 上皮伤口闭合但也存在明显的疤痕，以及穿孔的危险。 间充质细胞具有显着的再生、免疫调节和抗疤痕作用 基质细胞（MSC）已在许多研究中得到证实，其中一些是由我们进行的 团队。大量研究表明，MSCs的治疗作用主要是通过介导 通过他们的分泌因子。我们根据MSC衍生优化了治疗策略 加速角膜伤口愈合并限制不必要的炎症的因素（分泌组） 临床前模型中的继发性疤痕。这项拟议的临床试验将解决之间的差距 这些广泛的实验室研究取得了有希望的结果以及 MSC 的临床应用 分泌因素。我们提出了一种利用 MSC 分泌蛋白组作为滴眼剂的新疗法 加速角膜伤口不愈合患者的角膜伤口愈合。 临床级 MSC 将在伊利诺伊大学干细胞实验室中使用 制定了符合 FDA 要求的方案。 Secretome将被收集并冷冻 装在小瓶中，随后解冻，由药房在 每周一次。 MSC Secretome 将以一滴的形式涂抹在受影响的眼睛上，每天四次 除了研究者指示的标准护理支持治疗之外。阶段 I 安全性研究将涉及 12 名患者，他们将接受 2、4 或 8 周的分泌组治疗，以达到 每周随访评估安全性和耐受剂量。在此之后，附加 12 名患者（患者的不同子集）组成的一组将被纳入并获得最多 可耐受的治疗持续时间，以进一步评估治疗的安全性和有效性 每周随访，作为未来可能研究的初步数据。 在这些研究结束时，我们将获得有关该药物安全性的宝贵信息 治疗方法，以及有关伤口愈合功效的初步数据。 这些将促进基于干细胞的新型疗法的开发，用于管理 角膜和其他组织的伤口愈合障碍导致视力丧失。