Response: Before clinical translation, we will further characterize our mouse model of skin therapy, for the potential immune reaction, stability of skin grafts, and duration of the therapeutic effects in vivo.
"Overall, I think it's a very neat solution to this problem here of delivery of GLP-1 for the treatment of type 2 diabetes and obesity", says Jeff Millman, a biomedical engineer and stem cell researcher at Washington University in St. Louis, who was not involved in the study. They then inserted this gene into mouse skin cells in a dish, and developed them into skin grafts that could be transplanted onto mice, letting the modified hormone get into their blood.
This approach is now standard.
The study is the first to show that an engineered skin graft can survive long term in wild-type mice with intact immune systems.
In fact, skin cell transplants look to be an ideal way to deliver gene therapy. After the patches were grown and transplanted into mice, the animals were given the antibiotic, which fired up the enzyme and subsequent insulin production. Using CRISPR and skin grafts, researchers boost insulin levels to reduce weight. To test the process diabetes was chosen as the target illness as it can be treated through strategically delivered proteins. In this case, the progenitor cells were programmed to turn into cells that can release the hormone glucagon-like peptide-1 (GLP-1).
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The extra insulin removes excessive glucose from the bloodstream, preventing the complications of diabetes.
Using CRISPR, a tool which acts like molecular scissors, the team inserted one mutation which extended the hormone's life in the blood stream, and fused the modified gene to an antibody fragment so that it would circulate in the blood stream longer. We circumvented the technical issues by building a novel skin organoid culture system in vitro.
Xiaoyang Wu: The mouse skin transplantation system has not been well established before. The skin grafts can also be engineered to be immunocompatible with hosts to lower the chances of graft rejection. This promptly increased blood-insulin levels and reduced blood-glucose levels. But when the mice also were fed doxycycline so they secreted GLP-1, they gained less weight, showing the gene therapy was successful.
It will be relatively easy to translate this into a treatment for people, because skin grafts have been used to treat burn wounds for many years, says Wu.
Wu and other research groups are also looking at whether certain genetic disorders, such as hemophilia and others in which a patient's body is deficient of specific molecules, could be helped by therapeutic skin grafts. "Or it could function as a metabolic sink, removing various toxins", he said.