Skin graft gene therapy could treat obesity and diabetes

Researchers use CRISPR and skin grafts to boost insulin levels and reduce weight in mice.

In a new study, researchers at the University of Chicago have provided proof of concept for a new form of gene therapy that is administered via a skin transplant. In the study, they treated type-2 diabetes and obesity in mice by inserting the gene for a glucagon-like peptide 1 (GLP1) that stimulates the pancreas to secrete insulin. The extra insulin can prevent diabetes complications by removing excessive glucose from the bloodstream. It can also delay gastric emptying and reduce appetite.

We spoke to one of the study’s authors, Xiaoyang Wu, about the work. 

ResearchGate: What motivated this study?

Xiaoyang Wu: We have been working on skin somatic stem cells for a long time. As one of the most studied adult stem cell systems, skin stem cells have several unique advantages as the novel vehicle for somatic gene therapy. For one, the system is well established. Human skin transplantation using a CEA device developed from skin stem cells has been used clinically for decades for burn wound treatment, and is proven to be safe and effective.

RG: Can you tell us what you achieved?

Xiaoyang Wu: We established a novel mouse to mouse skin transplantation system to test skin gene therapy. In the proof-of-concept study, we showed that we can achieve the systematic release of GLP1 at therapeutic concentration by engineered skin grafts.

RG: How does this work to treat obesity and diabetes?

Xiaoyang Wu: When engineered to express therapeutic hormones, such as GLP1, the skin grafts can be used to suppress body weight gain, and development of type 2 diabetes.

RG: What were some of the challenges in development? How did you overcome them?

Xiaoyang Wu: The mouse skin transplantation system has not been well established before. We circumvented the technical issues by building a novel skin organoid culture system in vitro.

RG: Are there alternate methods to delivery this type of therapy, and if so why is skin better?

Xiaoyang Wu: The GLP1 receptor agonist can be applied with an injection, but the half-life will be short. Skin based gene delivery provides a long term and safe way for drug delivery in vivo.

RG: Do think this would have a similar effect in humans?

Xiaoyang Wu: Our proof-of-concept work demonstrated it’s possible to use engineered skin grafts to treat many non-skin diseases. Clinical translation of our findings will be relatively easy, as skin transplantation in human patients has been well established and clinically used for treatment of burn wounds for many years.

RG: What’s next for your research?

Xiaoyang Wu: Before clinical translation, we will further characterize our mouse model of skin therapy, looking at potential immune reaction, stability of skin grafts, and duration of the therapeutic effects. We are also interested in using our mouse model to test other potential applications of skin gene therapy, such as human genetic diseases, including hemophilia and urea cycle disorders.



Featured image courtesy of Mehmet Pinarci.