Study of the Safety, Tolerability, and Efficacy of an iPS Cell-based Therapy for Recessive Dystrophic Epidermolysis Bullosa Delivered with a Spray on Skin Device

使用皮肤喷雾装置治疗隐性营养不良性大疱性表皮松解症的 iPS 细胞疗法的安全性、耐受性和有效性研究

• 批准号: 10721324
• 负责人: Anna Lee Bruckner
• 金额: $ 53.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10721324
• 关键词: Adhesions; Adult; Adverse effects; Adverse event; Affect; Aftercare; Anemia; Antibodies; Appearance; Area; Back; Biological Assay; Biopsy; Bulla; COL7A1; Cell Therapy; Cells; Chronic; Cicatrix; Clinical Trials; Collagen; Consent Forms; Contracture; Cyclic GMP; Data; Dermis; Development; Devices; Disease; Disease remission; Electron Microscopy; Engraftment; Enrollment; Epidermolysis Bullosa Dystrophica; Epithelium; Esophageal Stenosis; Failure to Thrive; Fibroblasts; Fingers; Foundations; Graft Survival; Health; Histologic; Immune response; Immunofluorescence Microscopy; Immunologic Monitoring; Individual; Inflammation; Interview; Joints; Laboratories; Life Expectancy; Malignant - descriptor; Measures; Medical; Mendelian disorder; Microstomia; Monitor; Mucous Membrane; Mutation; Natural regeneration; Nutritional Support; Organ; Osteopenia; Osteoporosis; Outcome; Palliative Care; Patient Monitoring; Patients; Physical Examination; Preparation; Process; Production; Protocols documentation; Recurrence; Retroviral Vector; Risk; Safety; Skin; Skin graft; Squamous cell carcinoma; Standardization; Surface; Symptoms; System; Teratoma; Time; Toes; Transplantation; Treatment Efficacy; Work; chronic wound; clinical efficacy; cost; cost effective; digital; effective therapy; extrastriate visual cortex; healing; high risk; immunoreaction; induced pluripotent stem cell; keratinocyte; meetings; novel; open wound; phase 1 study; rare genetic disorder; safety assessment; safety study; screening; standard of care; stem cell therapy; treatment site; wound; wound care; wound closure; wound healing

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder characterized by fragility of the skin and mucous membranes. Affected individuals are born with open wounds and blisters which become recurrent and/or chronic over time. Both the skin and mucosal epithelia heal with scarring, causing fusion of the fingers and toes (pseudosyndactyly) and joint contractures, microstomia, and esophageal strictures. Non-skin complications include failure to thrive, anemia, and osteopenia/osteoporosis. The course of RDEB is unremitting, and patients surviving into adulthood have a high risk of developing aggressive squamous cell carcinomas that can be fatal. Shortened life-expectancy is the norm for patients with RDEB. There is no approved disease-modifying treatment for RDEB. Current therapies are palliative and focus on promoting wound healing, nutritional support, and treating complications as early as possible. RDEB is caused by mutations in COL7A1, leading to absence or deficiency of functional collagen VII (Col7), an integral component in the adhesion of epithelia to dermis in the skin and mucous membranes. Remission from the open wounds of RDEB could be obtained if functional Col7 is replaced in the skin. However, a durable remission can only be attained if an affected patient’s cells are genetically corrected, and a sufficient number of renewable cells engraft back into wounds. This pilot, phase 1 study will evaluate the safety and efficacy of one such approach in patients with RDEB who have the common mutation c.7485+5G>A. Using an ex vivo approach, the patient’s skin cells will be genetically corrected and reprogrammed into induced pluripotent stem cells (iPSCs) in an efficient one step process. The iPSCs will be differentiated into functional keratinocytes and fibroblasts expressing Col7. These keratinocytes and fibroblasts will be transplanted to the patient using a novel Spray-on-Skin device developed by AVITA Medical. The primary objective of this study is to evaluate the safety of this treatment approach. After treatment, patients will be monitored for 1 year for the development of squamous cell carcinoma or teratomas within the treated areas, immune reactions, and other adverse events. The secondary objectives are to provide proof-of- concept data that the use of genetically corrected iPSC-derived keratinocytes and fibroblasts will function normally and are an effective treatment for chronic wounds in patients with RDEB. The expression of Col7 and formation of anchoring fibrils after treatment will be evaluated. In addition, wound closure and the durability of wound closure compared to standard wound care will be studied. We hypothesize that this treatment will be safe and well-tolerated and lead to the regeneration of histologically normal skin expressing Col7 that is not prone to re-wounding. If successful, this work will lay the foundation for the development of iPSC-based therapies for other monogenic diseases affecting internal organs, where the difficulty in monitoring adverse effects of an iPSC-based therapy would make them unlikely first targets.

隐性营养不良表皮溶解球杆（RDEB）是一种罕见的遗传疾病，其特征是脆弱性 皮肤和粘膜。受影响的人天生有开放的伤口和水泡 随着时间的流逝而复发和/或慢性。皮肤和粘膜上皮都可以通过疤痕愈合，导致 手指和脚趾融合（假性粘合）和关节染色，微骨和食管 狭窄。非皮肤并发症包括未能繁殖，贫血和骨质减少症/骨质疏松症。课程 RDEB不懈，患者生存到成年 可能致命的鳞状细胞癌。缩短寿命缩短是患者的常态 rdeb。 RDEB没有批准的疾病改良治疗方法。当前的疗法是姑息治疗的，专注于 促进伤口愈合，营养支持和尽早治疗并发症。 RDEB是由COL7A1突变引起的，导致功能性胶原蛋白VII的缺乏或缺乏 （COL7），上皮粘附在皮肤和粘膜中真皮的粘附中的组成部分。 如果更换功能性COL7，则可以从RDEB的开放伤口中缓解。 皮肤。但是，只有在受影响的患者的细胞中，才能附加持久的缓解 经过校正，足够数量的可再生细胞植入了伤口中。这项飞行员1阶段研究将 评估具有常见的RDEB患者的一种此类方法的安全性和效率 突变C.7485+5G> a。使用离体方法，患者的皮肤细胞将得到遗传纠正，并且 在有效的一步过程中重新编程为诱导的多能干细胞（IPSC）。 IPSC将 分化为表达COL7的功能性角质形成细胞和成纤维细胞。这些角质形成细胞和成纤维细胞 将使用Avita Medical开发的新型皮肤装置将其移植给患者。 这项研究的主要目的是评估这种治疗方法的安全性。治疗后， 将监测患者1年以开发鳞状细胞癌或畸胎瘤。 治疗区域，免疫反应和其他不良事件。次要目标是提供证明 使用一般校正的IPSC衍生角质形成细胞和成纤维细胞的概念数据将起作用 通常，是RDEB患者的慢性伤口的有效治疗方法。 Col7和 将评估治疗后锚定纤维的形成。另外，伤口闭合和耐用性 与标准伤口护理相比，伤口闭合将进行研究。我们假设这种治疗将是 安全且耐受性良好，并导致组织学正常皮肤表达Col7的再生 容易重新打球。如果成功，这项工作将为基于IPSC的发展奠定基础 影响内部器官的其他单基因疾病的疗法，监测逆境的困难 基于IPSC的疗法的影响将使它们不太可能成为第一个靶标。