Gene Transfer for Recessive Dystrophic Epidermolysis Bullosa

基因转移治疗隐性营养不良性大疱性表皮松解症

• 批准号: 8126248
• 负责人: PAUL KHAVARI
• 金额: $ 66.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126248
• 关键词: Achievement; Affect; Animal Model; Arthritis; Autologous; Back; Basement membrane; Basic Science; Bulla; Caring; Cell Therapy; Cell Transplants; Cells; Cessation of life; Child; Cicatrix; Clinic; Clinical Trials; Collagen Type VII; Cutaneous; Development; Effectiveness; Engineering; Engraftment; Enrollment; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Failure; Family; Gene Delivery; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Transfer; Genetic; Genetic Skin Diseases; Genomics; Goals; Health; Hereditary Disease; Human; Immune; Immune response; In Vitro; Individual; Infection; Inherited; Institutes; Lead; Life Expectancy; Measures; Mission; Molecular; Molecular Profiling; Mucous Membrane; Mus; Musculoskeletal Diseases; Organ failure; Other Genetics; Pain; Persons; Phase; Phase I Clinical Trials; Proteins; Reaction; Research; Retroviridae; Severity of illness; Skin; Skin Tissue; Skin Transplantation; Skin graft; Squamous cell carcinoma; Staging; Therapeutic; Tissue Grafts; Transplantation; base; candidate identification; follow-up; gene correction; gene therapy; insight; keratinocyte; mRNA Expression; palliative; protein expression; restoration; skin disorder; success; technology development; vector; wound

DESCRIPTION (provided by applicant): Epidermolysis bullosa (EB) is a family of inherited genetic blistering skin disorders. Children lacking normal type VII collagen develop a severe, scarring EB subtype, recessive dystrophic epidermolysis bullosa (RDEB), which produces painful blisters and wounds on skin and mucous membranes. RDEB subjects have a shortened life expectancy with early death from infection, organ failure or squamous cell carcinoma (SCC). Current therapy for RDEB is limited to palliative wound care as there are no therapies available that alter the course or severity of the disease. We have focused on developing molecular therapy for RDEB. We have demonstrated that genetically corrected RDEB keratinocytes engineered to express type VII collagen can correct human RDEB skin tissue grafted onto immune deficient mice. We now plan to extend this approach to RDEB subjects by grafting genetically corrected autologous RDEB keratinocytes back into the skin of RDEB subjects in a human gene transfer clinical trial. The Specific Aims of this application are to deliver type VII collagen to the skin of RDEB subjects and to evaluate the effectiveness and duration of the beneficial effect. This R01 application documents our previous long term success in animal models, our gene transfer technology development, and our current plan to identify and enroll subjects for a Phase 1 clinic trial. Successful gene transfer will produce type VII collagen protein correctly localized to the cutaneous BMZ that is incorporated into ultrastructurally normal anchoring fibrils. We will assess the durability of type VII collagen at the levels of genomic retention, as well as mRNA and protein expression. We will evaluate gene expression profiles of the original and the gene corrected skin. We will evaluate grafted skin for unwanted immune response to the delivered type VII collagen protein. Analysis for any humoral or cellular immune responses in RDEB recipients of genetically corrected autologous skin grafts will provide important information both about the likelihood of success of this approach as well as insight into any failure of durability. This application fulfills the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases through focused research upon treatment of this severe skin disease by translational application of previous basic science successes. We expect that this trial may lead to a potentially effective cell based therapy for these subjects and may further support corrective gene therapy for genetic skin diseases. PUBLIC HEALTH RELEVANCE: This application proposes to develop gene therapy for a severe skin disease called recessive dystrophic epidermolysis bullosa (RDEB). We plan to correct the affected person's own skin cells and transplant their own cells back onto their skin. Effective gene therapy in this skin disease will assist in development of gene therapy for other genetic diseases.

描述（由申请人提供）：表皮溶解Bullosa（EB）是一个遗传性遗传起泡的皮肤疾病的家族。缺乏正常型VII胶原蛋白的儿童会出现严重的疤痕亚型，隐性营养不良的表皮溶质bullosa（RDEB），后者会在皮肤和粘膜上产生疼痛的水泡和伤口。 RDEB受试者的预期寿命缩短，感染，器官衰竭或鳞状细胞癌（SCC）死亡。 RDEB的当前疗法仅限于姑息伤口护理，因为没有可改变疾病病程或严重性的疗法。我们专注于为RDEB开发分子疗法。我们已经证明，经过遗传校正的RDEB角质形成细胞设计为表达VII型胶原蛋白可以纠正移植到免疫缺陷小鼠上的人类RDEB皮肤组织。现在，我们计划通过在人类基因转移临床试验中将遗传校正的自体RDEB角质形成细胞接收到RDEB受试者的皮肤，将这种方法扩展到RDEB受试者。本应用的具体目的是将VII型胶原蛋白递送至RDEB受试者的皮肤，并评估有益效应的有效性和持续时间。此R01应用程序记录了我们以前在动物模型，基因转移技术开发以及当前识别和注册1期诊所试验对象的计划中的长期成功。成功的基因转移将产生VII型胶原蛋白正确定位于皮肤BMZ，该蛋白被掺入超大型正常锚固纤维中。我们将评估VII型胶原蛋白在基因组保留水平以及mRNA和蛋白表达水平上的耐用性。我们将评估原始和基因校正皮肤的基因表达谱。我们将评估移植的皮肤，以实现对递送的VII型胶原蛋白的不良免疫反应。分析遗传校正自体皮肤移植物的RDEB受体中的任何体液或细胞免疫反应都将提供有关这种方法成功可能性的重要信息，以及对任何耐用性失败的洞察力。该应用通过重点研究对这种严重的皮肤疾病的治疗，通过转化以前的基础科学成功的应用来履行国家关节炎和肌肉骨骼和皮肤疾病的使命。我们预计该试验可能会导致对这些受试者的潜在有效的基于细胞的疗法，并可能进一步支持遗传性皮肤疾病的纠正基因治疗。公共卫生相关性：该应用建议为一种称为隐性营养不良表皮溶质bullosa（RDEB）的严重皮肤疾病开发基因疗法。我们计划纠正受影响的人自己的皮肤细胞，并将自己的细胞移植回皮肤。在这种皮肤病中有效的基因疗法将有助于开发其他遗传疾病的基因治疗。