Exploring Alternative iPS Cell Therapies for Recessive Dystrophic Epidermolysis Bullosa

探索隐性营养不良性大疱性表皮松解症的替代 iPS 细胞疗法

• 批准号: 9811321
• 负责人: Ganna Bilousova
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811321
• 关键词: Address; Adult; Affect; Back; Basement membrane; Biopsy; Bulla; Cell Differentiation process; Cell Therapy; Cells; Cessation of life; Charities; Cicatrix; Clinic; Clinical; Clinical Trials; Collagen Type VII; Colorado; Complication; Cutaneous; Cyclic GMP; Data; Deposition; Dermis; Devices; Differentiated Gene; Disease; Engraftment; Enteral Feeding; Epidermis; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Epithelium; FDA approved; Fibroblasts; Foundations; Funding; Gene Delivery; Generations; Genes; Goals; Guidelines; Immune; Inflammation; Inherited; Injury; Investigational Drugs; Letters; Medical; Medical Research; Mesenchymal; Mesenchymal Stem Cells; Methods; Mutation; Organ; Outcome; Patients; Phenotype; Production; Protocols documentation; Regenerative Medicine; Research; Risk; Safety; Science; Severities; Skin; Skin graft; Source; Stem cells; Stromal Cells; System; Testing; Time; Tissues; Translating; Transplantation; Universities; Validation; Wound Healing; base; catalyst; clinical development; cost; effective therapy; gastrointestinal; gene correction; healing; improved; induced pluripotent stem cell; innovation; keratinocyte; meetings; member; novel; novel strategies; risk benefit ratio; stem; stem cell differentiation; stem cell therapy

Project Summary No effective treatments are available for epidermolysis bullosa (EB), a group of rare inherited skin blistering disorders that can be devastating, and in some cases lethal. The ability to reprogram adult skin cells into induced pluripotent stem cells (iPSC) now offers the possibility of developing a permanent corrective therapy for EB. Our advances in developing safer and more efficient reprogramming, gene editing and iPSC differentiation protocols allowed us to establish the “EB iPS Cell Consortium” comprised of the University of Colorado (Drs. Roop, Bilousova, Kogut and Bruckner), Stanford University (led by Dr. Oro) and Columbia University (led by Dr. Christiano). The Consortium is currently developing an iPSC-based therapy for the severe recessive dystrophic form of EB (RDEB) that is comprised of gene-corrected epidermal sheets and composite skin grafts. The current application will explore two novel iPSC therapies for RDEB, and the non- profit foundations that currently sponsor the Consortium, the EB Research Partnership, the EB Medical Research Foundation and the Cure EB Charity, have agreed to provide the required 1 to 1 matching funds for this RFA submission. Although skin grafts may be the fastest path forward to demonstrate safety and efficacy of an iPSC-based therapy for RDEB patients, the time required to generate these grafts from genetically corrected iPSCs is lengthy and consequently expensive. Therefore, we are proposing to evaluate a “spray-on- skin” delivery system developed by Avita Medical, for delivering skin cells differentiated from gene-edited RDEB iPSCs as a more straightforward alternative to skin grafts. If successful, the “spray-on-skin” delivery system would decrease the time to patient application vs. the time and cost it takes to grow epidermal and composite grafts and would potentially produce superior outcomes for EB patients due to the lower risk of inflammation and scarring. In addition, while gene-corrected iPSC-derived keratinocytes may correct the cutaneous phenotype in RDEB patients, these cells will not be effective in treating the severe gastrointestinal manifestations associated with RDEB, which often require the use of feeding tubes. Therefore, we will also assess if the systemic delivery of gene-corrected-iPSC-derived mesenchymal stem cells (MSCs) can facilitate wound healing in both internal epithelia and the skin. If effective, the systemic delivery of MSCs would not only revolutionize how we treat EB patients, but also potentially represent a novel approach to treat many systemic multifocal diseases and injuries that affect internal organs and tissues. The following aims are proposed: Aim 1 will generate gene-corrected iPSC-derived fibroblasts and MSCs under cGMP-compliant conditions. Aim 2 will explore the feasibility of using the “spray on skin” device to deliver gene-corrected iPSC-derived keratinocytes and fibroblasts. Aim 3 will assess the ability of systemically delivered MSCs to improve wound healing in the skin and internal epithelia. Aim 4 will generate preliminary safety and efficacy data for the FDA.

项目摘要 没有有效的治疗疗法可用于表皮溶解球杆（EB），这是一组稀有的遗传性皮肤 可能是毁灭性的疾病，在某些情况下是致命的。重新编程成人皮肤细胞的能力 现在进入诱导的多能干细胞（IPSC）现在提供了开发永久纠正措施的可能性 EB的治疗。我们开发更安全，更有效的重编程，基因编辑和IPSC的进步 分化协议使我们能够建立大学包括的“ EB IPS细胞财团” 科罗拉多州（鲁普博士，比洛索瓦，科格特和布鲁克纳），斯坦福大学（由Oro博士领导）和哥伦比亚大学 大学（由克里斯蒂安诺博士领导）。该财团目前正在开发一种基于IPSC的疗法 EB（RDEB）的严重隐性营养不良形式，该形式已完成基因校正的表皮片和 复合皮肤移植物。当前的应用程序将探索两种新型的IPSC疗法，用于RDEB，非 - 目前赞助财团，EB研究合作伙伴关系，EB医学的利润基础 研究基金会和Cure EB慈善机构已同意为所需的1比1匹配资金 此RFA提交。尽管皮肤移植物可能是表现出安全性和轻松性的最快前进道路 针对RDEB患者的基于IPSC的治疗，从遗传上产生这些移植物所需的时间 校正的IPSCS很长，因此昂贵。因此，我们提议评估“喷雾” 由Avita Medical开发的皮肤”输送系统，用于递送与基因编辑的皮肤细胞 RDEB IPSC是皮肤移植物的更直接替代品。如果成功，则“喷涂”交付 系统将减少患者申请的时间与增加表皮和成本的时间和成本 复合移植物，由于较低的风险 此外，尽管经过基因校正的IPSC衍生的角质形成细胞可能会纠正 RDEB患者的皮肤表型，这些细胞将无效治疗严重的胃肠道 与RDEB相关的表现通常需要使用进料管。因此，我们也会 评估基因矫正-IPSC衍生的间充质干细胞（MSC）的全身递送是否可以促进 内部上皮和皮肤的伤口愈合。如果有效，MSC的系统交付不仅将 彻底改变了我们如何治疗EB患者，但也有可能代表一种治疗许多系统性的新方法 影响内部器官和组织的多灶性疾病和损伤。提出了以下目标：目标1 将在CGMP兼容条件下生成经过基因校正的IPSC衍生的成纤维细胞和MSC。 AIM 2意志 探索使用“在皮肤上的喷雾”设备提供基因校正的IPSC衍生角质形成细胞的可行性 和成纤维细胞。 AIM 3将评估系统地交付的MSC改善伤口愈合的能力 皮肤和内部上皮。 AIM 4将为FDA生成初步的安全性和效率数据。