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.

Public Health Relevance

Project Summary Gene therapy with adult stem cells isolated from skin can be used for treatment of a variety of otherwise terminal or severely disabling diseases. However, development of clinically relevant skin stem cell therapy remains challenging to the field due to lack of a good animal model to test the efficacy and safety of potential therapy in vivo. We have now resolved the technical hurdles and developed a new mouse model for skin stem cell therapy. In this proposal, we will take advantage of this novel platform and explore the feasibility and clinical potential of skin gene therapy for treatment of phenylketonuria and hemophilia, two inherited human diseases. Our results will provide an important proof-of-concept and serve as the basis for development of effective therapeutic strategies with skin stem cells targeting various diseases in the future.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project (R01)
Project #
5R01OD023700-04
Application #
9842019
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mirochnitchenko, Oleg
Project Start
2017-03-01
Project End
2021-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Lee, Jimmy; Lee, Philbert; Wu, Xiaoyang (2017) Molecular and cytoskeletal regulations in epidermal development. Semin Cell Dev Biol 69:18-25
Zhang, Yao; Ho, Andy; Yue, Jiping et al. (2014) Structural basis and anticancer properties of ruthenium-based drug complexed with human serum albumin. Eur J Med Chem 86:449-55