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

摘要 无法愈合的角膜创伤是一种具有挑战性的疾病，治疗选择有限，可以 会导致严重的视力丧失。它们可以在许多情况下发生，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)角膜功能不足 干细胞(例如，在严重损伤或自身免疫性疾病之后)。目前可用的治疗方法 受到无法显著促进组织修复和防止病理反应的限制 包括溃疡/融化和疤痕/纤维化。结果，不仅出现了显著的延迟， 上皮性伤口闭合，也有明显的疤痕，并有穿孔的风险。 间充质细胞的显著再生、免疫调节和抗瘢痕作用 基质细胞(MSCs)已经在许多研究中被发现，其中一些是由我们的 一队。大量研究表明，骨髓间充质干细胞的治疗作用主要是通过介导的。 通过他们的秘密因素。我们优化了基于MSC派生的治疗策略 促进角膜伤口愈合和限制不必要炎症的因子(分泌体) 临床前模型中的继发性瘢痕形成。这项拟议的临床试验将解决 这些广泛的实验室研究结果和MSC的临床应用前景看好 隐藏的因素。我们提出了一种新的治疗方法，将MSC分泌组用作滴眼剂 加速未愈合的角膜伤口患者的角膜伤口愈合。 临床级别的MSC将在伊利诺伊大学干细胞实验室使用 建立了符合FDA要求的方案。分泌物将被收集并冷冻 小瓶，稍后将解冻，由药房在 每周一次。MSC分泌素每日四次，每次一滴，用于患眼 除了标准的护理外，还应按照研究人员的指示进行支持性治疗。这一阶段 I安全性研究将涉及12名患者，他们将接受2周、4周或8周的分泌素治疗 每周随访评估安全性和耐受量。在此之后，又增加了一个 12名患者(不同的患者亚组)将被纳入并接受最大限度的 可耐受的疗程，以进一步评估治疗的安全性和有效性 每周随访一次，作为未来可能研究的初步数据。 在这些研究结束时，我们将获得关于这一安全的有价值的信息 治疗方法，以及在伤口愈合方面的疗效的初步数据。 这些将促进以干细胞为基础的新疗法的开发，以管理 可视致残的角膜和潜在其他组织的伤口愈合障碍。

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.