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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要大疱性表皮松解症（EB）是一种罕见的遗传性皮肤病，目前尚无有效的治疗方法起泡性疾病可能是毁灭性的，在某些情况下甚至是致命的。重新编程成人皮肤细胞的能力。诱导多能干细胞 (iPSC) 现在提供了开发永久性矫正的可能性我们在开发更安全、更高效的重编程、基因编辑和 iPSC 方面取得的进展。分化协议使我们能够建立“EB iPS 细胞联盟”，由大学组成科罗拉多州（Roop、Bilousova、Kogut 和 Bruckner 博士）、斯坦福大学（由 Oro 博士领导）和哥伦比亚大学大学（由 Christiano 博士领导）目前正在开发一种基于 iPSC 的疗法。严重隐性营养不良型 EB (RDEB)，由基因校正的表皮片和目前的申请将探索两种新型 iPSC 疗法用于 RDEB 和非复合皮肤移植。目前赞助该联盟、EB 研究合作伙伴、EB 医疗的盈利基金会研究基金会和 Cure EB 慈善机构已同意提供所需的 1 对 1 配套资金尽管皮肤移植可能是证明安全性和有效性的最快途径。对 RDEB 患者进行基于 iPSC 的治疗时，从基因上生成这些移植物所需的时间校正的 iPSC 时间较长，因此价格昂贵，因此，我们建议评估“喷雾”。由Avita Medical开发的“皮肤”输送系统，用于输送基因编辑分化的皮肤细胞 RDEB iPSC 作为皮肤移植的更直接替代方案如果成功，将采用“皮肤喷雾”输送方式。与生长表皮和生长所需的时间和成本相比，系统将减少患者应用的时间由于复合移植物的风险较低，可能会为 EB 患者带来更好的结果此外，基因校正的 iPSC 衍生的角质形成细胞可能会纠正炎症和疤痕。由于 RDEB 患者的皮肤表型不同，这些细胞不能有效治疗严重的胃肠道疾病与 RDEB 相关的表现，通常需要使用饲管。评估基因校正 iPSC 衍生的间充质干细胞 (MSC) 的全身递送是否可以促进如果有效的话，间充质干细胞的全身输送不仅可以促进内部上皮和皮肤的伤口愈合。彻底改变了我们治疗 EB 患者的方式，而且也有可能代表一种治疗许多系统性疾病的新方法影响内脏和组织的多灶性疾病和损伤提出以下目标：目标 1。将在符合 cGMP 的条件下生成基因校正的 iPSC 衍生的成纤维细胞和 MSC。探索使用“皮肤喷雾”装置输送基因校正的 iPSC 衍生角质形成细胞的可行性目标 3 将评估全身输送的 MSC 改善伤口愈合的能力。 Aim 4 将为 FDA 生成初步的安全性和有效性数据。