It is widely accepted that A? peptides, the principal component of senile plaques, play a causative role in the pathogenesis of Alzheimer's disease (AD). Thus, the majority of potential disease-modifying treatments of AD are directed against A?, and the most elaborated approach is immunotherapy. Although passive immunization with intact antibody against A? can attenuate amyloid deposition and improve cognitive function in vivo, administration of antibodies will require intravenous delivery, chronic dosing, and high quantities, which increase the probability of adverse effects and costs of the therapy. In this regard, somatic gene therapy provides a promising therapeutic approach for treatment of AD. As the largest surface organ, human skin serves an ideal site for tissue engineering, as well as the long-term and efficient delivery of therapeutic genes in vivo. Compared to conventional gene therapy approaches, including viral vectors, transplantation with autologous skin grafts derived from epidermal stem/progenitor cells is technically well-established, minimally invasive, and has been successfully used for decades in the treatment of burn wounds. It has also been well documented that therapeutic molecules, including large proteins secreted by skin epidermal cells, can cross the epidermal/dermal barrier and reach the circulation to achieve therapeutic effects in a systemic manner. We have recently resolved the long-standing technical obstacle in the field by establishing a novel mouse skin organotypic culture and transplantation model. With this key technical advancement, we have demonstrated that cutaneous gene therapy with engineered epidermal progenitor cells can serve as a safe and effective treatment for many human diseases, including diabetes and substance abuse. 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 AD. Specifically, we will employ CRISPR (clustered regularly-interspaced short palindromic repeats) technology to engineer and develop skin epidermal progenitor cells with inducible expression of scFv (single-chain variable fragment) targeting A?. Upon transplantation of skin organoids derived from engineered cells, we will explore the potential therapeutic effects in AD model animals and examine the long-term stability and potential immune reactions of skin grafts. Together, our studies will establish a unique and powerful model of cutaneous gene therapy for treatment of AD, revealing the therapeutic potential for somatic gene therapy with epidermal progenitor cells.

Public Health Relevance

Although Alzheimer's disease (AD) is increasingly being recognized as one of the most important aging-associated diseases, only symptomatic treatments exist. In this proposal, we will explore the intriguing possibility that engineered skin grafts can be used to deliver therapeutic agents for treatment of AD. Our results will provide an important proof-of-concept and serve as the basis for development of effective AD therapy with skin stem cells in the future.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Research Project (R01)
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Mirochnitchenko, Oleg
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Yue, Jiping; Gou, Xuewen; Li, Yuanyuan et al. (2017) Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes. Cell Stem Cell 21:256-263.e4
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