An Innovative Cutaneous Gene Therapy Platform For Metabolic Disorders

SUMMARY

• The field of metabolic disease treatment has long been challenged by the need for precise, long-term regulation of critical hormones and proteins that manage glucose homeostasis and energy balance. Current therapeutic strategies for conditions such as obesity and diabetes struggle to provide a sustained and adjustable intervention, leaving patients with options that often require frequent dosing and invasive delivery methods. This creates an urgent demand for solutions that can deliver controllable, long-duration expression of therapeutic agents, ultimately enhancing treatment outcomes and patient quality of life.

• Existing approaches encounter significant limitations, including the inability to finely tune dosage levels and timing of protein release, resulting in inconsistent clinical benefits. Traditional gene and protein therapies often suffer from issues such as immune rejection, transient effectiveness, and potential adverse side effects. The lack of a dynamically regulated system hampers robust disease management, emphasizing the need for innovative strategies that address the complex challenges inherent in current metabolic disorder treatments.

The proposed solution: Skin stem therapy to stably deliver active GLP-1 in a dose-dependent manner promoting insulin release

• The faculty inventor developed employs CRISPR-mediated genome editing to insert a GLP-1-IgG-Fc fusion gene under a tetracycline-dependent promoter into epidermal progenitor cells. These cells, integrated into safe genomic loci in both mice and humans, secrete GLP-1 in a controllable, dose-dependent manner when doxycycline is administered. Skin grafts formed with these engineered cells maintain normal tissue function while delivering sustained and adjustable therapeutic protein levels, effectively promoting insulin secretion and improved metabolic responses.

• What sets this approach apart is its innovative combination of precision genome editing with a noninvasive, skin-based platform. The tetracycline-inducible system allows meticulous control over therapeutic protein dosage, adapting to patient needs and ensuring long-term stability with minimal risk of immune rejection or tumorigenesis.

FIGURE

ADVANTAGES

ADVANTAGES

• Controllable, dose-dependent therapeutic protein secretion

• Long-term stability and integration of the engineered skin grafts without immune rejection or tumorigenic risks

• Effective improvement in metabolic parameters such as enhanced insulin secretion, improved glucose tolerance, and reduced weight gain

• Epidermal stem cells can be readily engineered in vitro and standard procedures exist for transplantation

• Ease of access and cryopreservation of skin epidermal progenitor cells for durable applications

APPLICATIONS

• Cutaneous gene therapy for treatment of various metabolic disorders

•  Controlled diabetes therapy

• Obesity management

• Gene-edited skin grafts

PUBLICATIONS

• Yue J, Gou X, Li Y, Wicksteed B, Wu X. Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes. Cell Stem Cell. 2017 Aug 3;21(2):256-263.e4. doi: 10.1016/j.stem.2017.06.016. PMID: 28777946; PMCID: PMC5555372.

August 20, 2024

Proof of concept

Patent Pending

Licensing,Co-development

Xiaoyang Wu