Scientists at the University of Chicago have demonstrated that skin grafts engineered by CRISPR-mediated genome editing can be used to regulate blood glucose homeostasis for treatment of diabetes and obesity.
Scientists at University of Chicago (IL, USA) have developed a novel mouse-to-mouse skin transplantation model in a new approach to the delivery of gene-based therapies. They demonstrated how engineered mouse cells could increase insulin secretion and reverse high-fat-diet-induced weight gain and insulin resistance. The work presented in Cell Stem Cell earlier this month is the first to show the long term survival of skin transplants in immunocompetent mice.
The development of gene therapies has been greatly hindered by the lack of an appropriate mouse model to determine the potential outcomes of a gene therapy in vivo. In this study, a research team at the University of Chicago Medical Center designed a mouse-to-mouse skin transplantation model in animals with intact immune systems. The model was then used to show the clinical potential of gene therapy based on engineering epidermal progenitor cells.
The research was focused on the treatment of diabetes by the strategic delivery of specific proteins. The team inserted the gene for glucagon-like peptide 1 (GLP1), a hormone that stimulates insulin secretion, into epidermal progenitor cells. Using CRISPR, they modified the GLP1 gene to extend the hormone’s half-life in the blood stream and fused the modified gene to an antibody fragment to ensure it was present in the blood stream for longer. The modified gene also included an inducible promotor which allowed controlled secretion of GLP1 by exposure to antibiotic doxycycline.
The “skin-like organoid” was grown at an air/liquid interface and grafted onto mice with intact immune systems. There was no significant rejection of the transplanted skin and when the mice ate food containing minute amounts of doxycycline, GLP1 was released into the blood in a dose-dependent manner.
Researchers fed normal or gene-altered mice a high-fat diet which led to rapid weight gain. When doxycycline was introduced into the diet of gene-altered mice, the mice expressing GLP1 showed less weight gain, lowered glucose levels and reduced insulin resistance. This data strongly suggests that the cutaneous gene therapy developed by the Wu laboratory group could be utilized for the treatment and prevention of diet-induced obesity and pathologies.
What is more, engineering epidermal progenitor cells has been shown to be a potential long-lasting, safe and versatile approach to gene therapy.
“We think this can provide a long-term safe option for the treatment of many diseases,” explains Wu. “It could be used to deliver therapeutic proteins, replacing missing proteins for people with a genetic defect, such as hemophilia, or it could function as a metabolic sink, removing various toxins.”
Sources: Yue J, Gou X, Li Y, Wicksteed B, Wu X. Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes. Cell Stem Cell. 21(2), 256-263 (2017); www.sciencedaily.com/releases/2017/08/170803122728.htm