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

摘要 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， 导致严重视力丧失。它们可以发生在许多情况下，例如：（1）慢性丧失 神经，如糖尿病（2）感染性/免疫性溃疡，和（3）角膜， 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 受到不能显著促进组织修复和防止病理反应的限制 包括溃疡/融化和瘢痕形成/纤维化。结果，不仅在 上皮伤口闭合，但也存在显著的瘢痕形成和穿孔的风险。 间充质干细胞的显著再生、免疫调节和抗瘢痕形成作用 基质细胞（MSC）已在许多研究中显示，其中一些是由我们的研究人员进行的。 团队大量的研究表明，骨髓间充质干细胞的治疗作用主要是介导的 通过它们的分泌因子我们已经优化了基于MSC衍生的治疗策略， 促进角膜伤口愈合和限制不必要的炎症的因子（分泌蛋白质组）， 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以下方面的差距： 这些广泛的实验室研究结果和MSC的临床应用 分泌因子我们提出了一种新的治疗方法，利用MSC分泌蛋白作为滴眼剂， 加速角膜伤口未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使用 根据FDA要求制定方案。将收集并冷冻分泌组 在小瓶中，稍后将由药房解冻，单独分发给患者， 每周的基础上。MSC Secretome将以一滴的形式应用于受影响的眼睛，每天四次 除标准治疗支持疗法外，根据研究者的指示。相位 一项安全性研究将涉及12名患者，这些患者将接受2、4或8周的分泌蛋白组治疗， 通过每周随访访视评估安全性和耐受剂量。在此之后，一个额外的 将入组一组12例患者（不同的患者子集），并接受最大剂量的 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，我们将获得有关这种药物安全性的有价值的信息。 治疗方法，以及关于伤口愈合方面疗效的初步数据。 这些将促进开发新的基于干细胞的治疗方法， 角膜和潜在的其它组织的视觉上不能愈合的伤口。

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.