First in human phase I / II clinical trial of RAFT for aniridia related keratopathy.

眼睛前面的角膜是我们观察世界的窗口。如果透明度受损，可能会出现视力障碍甚至失明。无虹膜是一种罕见的致盲疾病（发病率为1：100，000），由PAX 6突变引起，PAX 6是负责眼睛发育和健康功能的基因之一。无虹膜相关性角膜病变（方舟）表现为角膜外上皮层（称为上皮）的持续性、慢性疼痛性缺陷。血管长入角膜，也会出现疤痕，这两者都会阻碍视力。方舟诱导的光敏感性可导致社会排斥。这些症状的原因与突变的角膜缘上皮干细胞（LESC）、基质细胞和组织无法维持正常的角膜上皮有关。目前的治疗方法包括全供体组织移植和培养LESC治疗，这两种方法的长期结果都很差。由于干细胞需要来自其环境中的邻近细胞和蛋白质的支持，因此单独移植培养的LESC可能不足以保护/改善患者的视力。最佳的方舟治疗包括移植健康的LESC和基质细胞（角膜支持组织）。我们提出的解决方案利用了我们的专利技术RAFT（真实的3D组织架构），其中LESC和基质细胞在可移植的胶原蛋白基质（人造组织）中一起培养。在我们的临床细胞治疗生产实验室中，我们能够按照被称为良好生产规范（简称GMP）的规定生产这种组织。临床前安全性研究支持我们向首次人体研究迈进。在本项目中，我们将进行1）在我们的Cells for Sight许可生产设施中进行RAFT的完整GMP方案验证，2）编写并提交获得临床试验监管批准所需的所有文件，3）在方舟患者中进行首次人体RAFT移植研究。在本I/II期临床试验中，我们将在21例方舟患者的一只眼睛中进行RAFT移植，以评估RAFT的安全性和初步疗效。结局指标将包括恢复正常角膜上皮，无任何缺陷、血管向内生长或瘢痕形成。如果成功，这种疗法可以为方舟患者提供急需的解决方案，也可以作为开发RAFT治疗其他致盲眼病的跳板。

The cornea on the front surface of the eye is our window to the world. If transparency is compromised, visual impairment and even blindness can occur. Aniridia is a rare blinding disease (1:100,000 incidence) caused by a mutation in PAX6 which is one of the genes responsible for development and healthy function of the eyes. Aniridia-related keratopathy (ARK) manifests as persistent, chronically painful defects of the outer epithelial layer of the cornea called the epithelium. Blood vessels grow into the cornea and scarring also occurs, both of which obstruct vision. ARK induced light sensitivity can lead to social exclusion. The cause of these symptoms is related to the inability of the mutated limbal epithelial stem cells (LESC), stromal cells and tissue to maintain normal corneal epithelium. Current treatments include whole donor tissue transplantation and cultured LESC therapy which have both shown poor long-term outcomes. Since stem cells require support from neighbouring cells and proteins in their environment, transplanting cultured LESC alone may not be sufficient to preserve / improve patient vision. An optimal ARK treatment would include transplantation of both healthy LESC and a stroma (corneal support tissue) populated with stromal cells. Our proposed solution utilises our patented technology known as RAFT (Real Architecture for 3D Tissues) in which LESC and stromal cells are cultured together in a transplantable collagen matrix (artificial tissue). We are able to make this tissue in compliance with the required regulations which are known as Good manufacturing practise, or GMP for short, in our clinical cell therapy production laboratory. Pre-clinical safety studies supports us moving forward to a first in human study. In this project we will undertake 1) full GMP protocol validation for RAFT in our Cells for Sight licensed manufacturing facility, 2) write and submit all of the documentation required to obtain regulatory approval for a clinical trial and 3) proceed to first in human RAFT transplantation studies in patients with ARK. In this phase I/II clinical trial we will perform RAFT transplantation in one eye of 21 ARK patients to assess RAFT safety and preliminary efficacy. The outcome measures will include restoration of a normal corneal epithelium without any defects, blood vessel ingrowth or scarring. If successful, this therapy could provide a much-needed solution for patients with ARK and also act as a springboard for the development of RAFT for other blinding eye diseases.