CRISPR Gene Therapy Can Be Applied Through the Skin to Reverse Obesity and Treat Diabetes

Gene edited mice expressing GLP1 on the left and normal mice on the right
Gene edited mice expressing GLP1 on the left and normal mice on the right

Researchers from the University of Chicago have developed a way to apply gene therapy via skin transplantation that could enable the reversal of obesity and the treatment of type-2 diabetes along with a myriad of other diseases.

The research punished on Thursday in the journal Cell Stem Cell, describes the team’s use of their novel form of gene therapy.

“We resolved some technical hurdles and designed a mouse-to-mouse skin transplantation model in animals with intact immune systems,” said study author Xiaoyang Wu, PhD, assistant professor in the Ben May Department for Cancer Research at the University of Chicago. “We think this platform has the potential to lead to safe and durable gene therapy, in mice and we hope, someday, in humans, using selected and modified cells from skin.”

The research is the first to demonstrate the successful long term survival of an engineered skin graft in mice with fully functioning immune systems. The team archived a greater than 80% success rate with their skin grafts.

Using CRISPR, the researchers edited the gene for glucagon-like peptide 1 (GLP1), which causes the pancreas to release insulin to remove excess glucose from the body. The gene has also been shown to reduce appetite by slowing the release of food from the stomach to into the small intestine.

Immunofluorescence
Immunofluorescence imaging shows normal skin differentiation and tissue architecture of transplanted skin grafts

A single edit was made to the gene that lengthens the half-life of glucagon-like peptide 1 in the blood. The gene was attached with an antibody fragment and an inducible promoter which allowed the researchers to turn on the gene at will using doxycycline in the food of mice.

The gene was the in inserted into skin cells of mice which were expanded in culture. Once the gene modified skin grafts were grown they were transplanted onto mice without showing any significant immune rejection.

When doxycycline was added to the food the gene edited mice showed an in increase blood-insulin levels and a reduction blood-glucose levels. The mice were fed a high-fat diet, the normal mice rapidly gained weight and became obese while the gene edited mice remained relatively slim and also showed reduced insulin resistance.

“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 researchers note, and they believe it could provide “significant benefits for the treatment of many human diseases,”.

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

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