Development of epidermal progenitor cell-based therapy for regenerative medicine

开发基于表皮祖细胞的再生医学疗法

基本信息

批准号：
9280088
负责人：
Xiaoyang Wu
金额：
$ 38.39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280088
关键词：
Anatomy Animal Model Animals Antibodies Autologous Transplantation Basement membrane Blood Circulation Blood Coagulation Disorders Blood Coagulation Factor Blood coagulation Cell Therapy Cells Classical phenylketonuria Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cutaneous Dermal Development Disease Ectopic Expression Engineering Engraftment Enzymes Epidermis Epilepsy Factor VIII Future Gene Delivery Genetic Engineering Hemophilia A Hepatic Hereditary Disease Human Immune system Immunocompetent Immunodeficient Mouse In Vitro Inborn Genetic Diseases Inherited Mediating Metabolic Metabolic Diseases Modeling Monitor Mus Mutation Organ Organoids Outcome Patients Phenotype Phenylalanine Phenylalanine Ammonia-Lyase Phenylalanine Hydroxylase Phenylketonurias Plasma Problem behavior Procedures Process Production Proteins Psyche structure Regenerative Medicine Research Safety Skin Skin Transplantation Somatic Gene Therapy Specificity Stem cell transplant Stem cells System Technology Testing Therapeutic Therapeutic Effect Tissue Therapy Tissues Transplantation Treatment Efficacy Work adult stem cell amino acid metabolism clinical application clinical development clinically relevant disability disabling disease efficacy testing gene therapy genetically modified cells genome editing human disease immunoreaction in vivo keratinocyte mouse model novel precise genome editing prevent regenerative therapy spatiotemporal stem cell therapy

项目摘要

Project Summary Somatic gene therapy provides a promising therapeutic approach for treatment of a variety of otherwise terminal or severely disabling diseases. The recent development of genome editing technology, including CRISPR (clustered regularly-interspaced short palindromic repeats) system, has made it possible to perform precise genetic engineering in cells. However, clinical application of CRISPR technology to human patients has been challenging due to the inadequate efficacy in vivo using conventional delivery approach. Thus, it is urgently needed to develop an ex vivo platform that can combine both precise genome editing in vitro with effective application of engineered cells in vivo. The epidermal progenitor cells of skin have several unique advantages, making it particularly suited for ex vivo gene therapy. Human skin is the largest and most accessible organ in the body, making it easy to isolate skin epidermal progenitor cells and monitor the tissue for potential detrimental complications. Anatomically, skin epidermis is separated from vasculature by the basement membrane, which prevents potential dissemination of genetically modified cell in vivo, making the potential therapy tissue specific and safe. Lastly, the potential applicability of cutaneous gene therapy is broad because it has been well documented that proteins expressed in skin epidermal cells can cross the epidermal/dermal barrier and reach circulation to achieve therapeutic effect in a systematic manner. In addition, ectopic expression of metabolic enzymes in skin epidermal cells can transform the engineered skin into a “metabolic sink” for correction of various metabolic disorders. However, despite the potential clinical importance, research in epidermal progenitor cell-based therapy (cutaneous gene therapy) has been greatly hindered due to lack of an appropriate mouse model. Although mouse or human skin can be transplanted to immunodeficient mice, lack of an intact immune system makes it impossible to examine the potential outcomes and complications that the therapy may elicit in vivo. We have now resolved the technical hurdle and established a unique mouse-to-mouse skin transplantation model that can stably introduce genome-edited epidermal progenitor cells into immunocompetent mice. In this proposal, we will take advantage of this novel platform and explore the feasibility and clinical potential of cutaneous gene therapy for treatment of genetic diseases, including phenylketonuria (PKU) and hemophilia A. Together, our studies will establish a unique and powerful model for cutaneous gene therapy with current genome editing technology, revealing the therapeutic potential for somatic gene therapy with epidermal progenitor cells.

项目概要体细胞基因治疗为治疗多种其他疾病提供了一种有前途的治疗方法基因组编辑技术的最新发展，包括晚期或严重致残疾病。 CRISPR（成簇规则间隔短回文重复序列）系统使执行然而，CRISPR技术在人类患者中的临床应用已经取得进展。由于使用传统的递送方法体内疗效不足，一直具有挑战性。迫切需要开发一个能够将体外精确基因组编辑与工程细胞在体内的有效应用。皮肤的表皮祖细胞有几个独特的优势，使其特别适合离体基因疗法。人类皮肤是体内最大且最容易接近的器官，因此很容易分离。皮肤表皮祖细胞并监测组织的潜在并发症。表皮通过基底膜与脉管系统分开，这防止了潜在的传播体内的基因改造细胞，使得潜在的治疗组织具有特异性和安全性。皮肤基因治疗的适用性很广泛，因为有充分的证据表明表达的蛋白质在皮肤表皮细胞中可以穿过表皮/真皮屏障到达循环达到治疗效果此外，皮肤表皮细胞中代谢酶的异位表达可以。将工程皮肤转变为“代谢池”，以纠正各种代谢紊乱。尽管具有潜在的临床重要性，基于表皮祖细胞的疗法（皮肤基因尽管小鼠或人类皮肤，但由于缺乏合适的小鼠模型，该疗法受到了极大的阻碍。可以移植到免疫缺陷小鼠体内，但由于缺乏完整的免疫系统，无法进行检查我们现在已经解决了该疗法在体内可能引起的潜在结果和并发症。攻克技术难关，建立了独特的小鼠间皮肤移植模型，可稳定导入在这项提议中，我们将利用基因组编辑的表皮祖细胞转化为具有免疫能力的小鼠。这个新平台并探索皮肤基因疗法治疗皮肤病的可行性和临床潜力遗传性疾病，包括苯丙酮尿症 (PKU) 和 A 型血友病。我们的研究将共同建立一个利用当前基因组编辑技术进行皮肤基因治疗的独特而强大的模型，揭示了表皮祖细胞体细胞基因治疗的治疗潜力。