Skin-targeted Cell Therapy for Recessive Dystrophic Epidermolysis Bullosa

隐性营养不良性大疱性表皮松解症的皮肤靶向细胞疗法

基本信息

批准号：
8639483
负责人：
Jakub Tolar
金额：
$ 43.71万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639483
关键词：
Adhesions Allogenic Autologous Binding Biochemical Biological Biology Body Surface Area Bone Marrow Cells Bulla Burn injury Cell Lineage Cell Therapy Cell model Cells Cessation of life Chemical Burns Chemicals Child Chronic Cicatrix Clinical Clinical Data Collagen Type VII Complex Connective Tissue Contracture Data Dermal Dermis Disease Effectiveness Engineering Epidermis Epidermolysis Bullosa Dystrophica Esophagus Extracellular Matrix Future Gene Targeting Gene Transfer Gene Transfer Techniques Genes Genetic Genome Goals Healed Healthcare Systems Hematopoietic Stem Cell Transplantation High Mobility Group Proteins Home environment Homing Human Human Genome Human Identifications Immune Inborn Genetic Diseases Individual Joints Knowledge Left Lesion Life Maintenance Marrow Mediating Medical Mesenchymal Metastatic Squamous Cell Carcinoma Methodology Methods Minor Modeling Mucous Membrane Mus Mutation Newborn Infant Nucleotides Oncogenic Opportunistic Infections Outcome Pain Patient Care Patients Physiological Platelet-Derived Growth Factor alpha Receptor Population Problem Solving Protein Deficiency Proteins Quality of life Regimen Risk Safety Sepsis Signal Transduction Site Skin Skin Tissue Squamous cell carcinoma Stem cells Structural Protein Structure System Technology Therapeutic Toxic effect Transgenes Translations Trauma Viral Viral Vector Wound Healing Wound Infection base biological systems cell type disease-causing mutation extracellular gene correction gene therapy genotoxicity healing high risk improved induced pluripotent stem cell injured insight loss of function mutation next generation novel nuclease overexpression polymerization pre-clinical premature protein expression public health relevance regenerative response restriction enzyme stem cell niche tissue repair tool vector

项目摘要

DESCRIPTION (provided by applicant): Recessive dystrophic epidermolysis bullosa (RDEB) is caused by loss-of-function mutations in the collagen type VII (C7) gene (COL7A1), and results in a potentially fatal and terribly debilitating disorder. Individuals with severe generalied RDEB develop blisters and erosions involving large portions of the body surface area, mutilating scarring, joint contractures, and strictures of the esophagus, with opportunistic infections and aggressive squamous cell carcinoma as principal causes of early death. We have shown that hematopoietic stem cell transplantation (HSCT) can increase C7 protein in skin and mucous membranes, and ameliorate many of the disease manifestations. Unfortunately not all mucocutaneous lesions heal, and the toxicities associated with HSCT are significant. Our overarching goal is to solve these problems by establishing a reliable method for delivering C7-expressing cells that home to the dermal-epidermal junction and secrete C7 protein. In order to accomplish this goal and to overcome the limitations of allogeneic HSCT, we will: 1) identify the optimal cellular vector and homing signal for targeting injured skin in RDEB, using human mesenchymal stromal/stem cells and induced pluripotent stem cells (iPSCs), 2) define the efficacy of systemic RDEB gene therapy by C7 gene augmentation, and 3) use nucleases for gene editing of individual mutations, as well as whole regions of the C7 gene. We propose to define the conditions conducive to wound healing in this severe blistering genodermatosis, but the impact of these studies may not be limited to RDEB. The function of C7 depends on extracellular polymerization, which makes RDEB an ideal model for understanding the mechanisms of cross- correction of structural protein deficiency in the extracellular matrix. In addition, wound healing integrates skin extracellular matrix and skin cells into a dynamic system, which in RDEB results in the depletion of skin stem cell niches and, in turn, provides a unique model of skin tissue repair with donor regenerative cells. By using powerful tools for studying and manipulating the information basis of biological systems-engineered restriction enzymes (nucleases), skin- targeting, and induced cell lineage conversion (iPSCs)-we will focus on developing personalized cell therapy for individuals with RDEB with the idea that our findings may have broad implications for understanding other connective tissue extracellular matrix diseases. Our proposal is equally motivated by wanting a better understanding of the biological mechanisms in injured skin and by needing to improve the lives of people with RDEB through maximizing the benefits and reducing the risks of potential novel therapies.

描述（由申请人提供）：隐性营养不良的表皮溶液Bullosa（RDEB）是由胶原型VII型（C7）基因（COL7A1）的功能丧失突变引起的，并导致潜在的致命且衰弱的疾病。患有严重重为RDEB的个体会出现水泡和侵蚀，涉及身体表面积的大部分，造成疤痕，关节染色和食管的狭窄，机会性感染和侵略性的鳞状细胞癌作为早期死亡的主要原因。我们已经表明，造血干细胞移植（HSCT）可以增加皮肤和粘膜中的C7蛋白质，并改善许多疾病表现。不幸的是，并非所有的粘膜皮肤病变都可以治愈，并且与HSCT相关的毒性很重要。我们的总体目标是通过建立可靠的方法来解决这些问题，以传递将C7的细胞表达为真皮 - 表皮结和分泌C7蛋白的细胞。 In order to accomplish this goal and to overcome the limitations of allogeneic HSCT, we will: 1) identify the optimal cellular vector and homing signal for targeting injured skin in RDEB, using human mesenchymal stromal/stem cells and induced pluripotent stem cells (iPSCs), 2) define the efficacy of systemic RDEB gene therapy by C7 gene augmentation, and 3) use nucleases用于单个突变以及C7基因的整个区域的基因编辑。我们建议定义在这种严重的生殖器病中有助于伤口愈合的疾病，但是这些研究的影响可能不仅限于RDEB。 C7的功能取决于细胞外聚合，这使得RDEB成为理解细胞外基质结构蛋白缺乏的机制的理想模型。此外，伤口愈合将皮肤外基质和皮肤细胞整合到动态系统中，在RDEB中导致皮肤干细胞壁ni的耗竭，进而为供体再生细胞提供了独特的皮肤组织修复模型。通过使用强大的工具来研究和操纵生物系统工程限制酶（核酸酶），皮肤靶向和诱导的细胞谱系转化率（IPSC）的信息基础 - 我们将专注于为RDEB患者开发个性化的细胞疗法，并认为我们的发现可能会对其他结构性互联网疾病进行广泛的影响。我们的建议同样是通过希望更好地了解受伤皮肤中的生物学机制，并需要通过最大程度地提高益处并降低潜在新型疗法的风险来改善RDEB的人的生活。