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August 10, 2017

Skin transplantation could be effective in battling diabetes, obesity

A novel approach with skin transplantation could enable a wide range of gene-based therapies to treat many human diseases such as diabetes. In a study in the journal Cell Stem Cell, Researchers from the University of Chicago provide ‘proof-of-concept’ for this claim. In their paper they describe gene-therapy administered through skin transplants to treat two related and extremely common human ailments: Type 2 diabetes and obesity.

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The proof-of-concept is a mouse-to-mouse skin transplantation model, using CRISPR technology, in animals with intact immune systems,” said study author Xiaoyang Wu, assistant professor in the Ben May Department for Cancer Research at the University of Chicago, in an article first published on Science Life.  “We think this platform has the potential to lead to safe and durable gene therapy in mice and, we hope, in humans, using selected and modified cells from skin.”

Mouse system less mature

As early as the 1970s, physicians learned how to harvest skin stem cells from a patient with extensive burn wounds, grow them in the laboratory and then apply the lab-grown tissue to close and protect a patient’s wounds. This approach is now standard. However, the application of skin transplants is better developed in humans than in mice. “The mouse system is less mature,” Wu explains. “It took us a few years to optimize our 3-D skin organoid culture system.”

This study is, according to the research team, the first to show that an engineered skin graft can survive long term in wild-type mice with intact immune systems. “We have a better than 80 percent success rate with skin transplantation,” Wu said. “This is exciting for us. We didn’t cure diabetes, but it does provide a potential long-term and safe approach of using skin epidermal stem cells to help people with diabetes and obesity better maintain their glucose levels.”

There is definitely a need to focus on diabetes. More than 100 million U.S. adults have either diabetes (30.3 million) or prediabetes (84.1 million), according the Centers for Disease Control and Prevention, more than two out of three adults are overweight. More than one out of three are considered obese.

Same approach for many diseases

The researchers also focused on diabetes because it is a common non-skin disease that can be treated by the strategic delivery of specific proteins.  But the same approach could eventually be used to treat a variety of metabolic and genetic conditions, not just diabetes. It’s a question of using skin cells to trigger different chemical reactions in the body.

The researchers inserted the gene for glucagon-like peptide 1 (GLP1), a hormone that stimulates the pancreas to secrete insulin. This extra insulin removes excessive glucose from the bloodstream, preventing the complications of diabetes. GLP1 can also delay gastric emptying and reduce appetite.
Using CRISPR, the GLP-1 gene could be tweaked to make its effects last longer than normal. The result was developed into skin grafts that were then applied to mice. Some 80 percent of the grafts successfully released the edited hormone into the blood, regulating blood glucose levels over four months, as well as reversing insulin resistance and weight gain related to a high-fat diet. Significantly, it’s the first time the skin graft approach has worked for mice not specially designed in the lab.

Practical and clinically relevant

“Together, our data strongly suggest that cutaneous gene therapy with inducible expression of GLP1 can be used for the treatment and prevention of diet-induced obesity and pathologies,” the authors wrote. When they transplanted gene-altered human cells to mice with a limited immune system, they saw the same effect. These results, the authors wrote, suggest that “cutaneous gene therapy for GLP1 secretion could be practical and clinically relevant.”

“We think this can provide a long-term safe option for the treatment of many diseases,” Wu said. “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.”

Skin progenitor cells have several unique advantages that are a perfect fit for gene therapy. Human skin is the largest and most accessible organ in the body. It is easy to monitor. Transplanted skin can be quickly removed if necessary. Skins cells rapidly proliferate in culture and can be easily transplanted. The procedure is safe, minimally invasive and inexpensive.

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