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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.

项目总结