Scientists have found a way to use skin transplants to administer gene-based therapies to treat common human ailments such as type-2 diabetes and obesity."We resolved some technical hurdles and designed a mouse-to-mouse skin transplantation model in animals with intact immune systems," said Xiaoyang Wu, assistant professor at the University of Chicago in the US.
"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," said Wu.
Beginning in the 1970s, physicians learned how to harvest skin stem cells from a patient with extensive burn wounds, grow them in the laboratory, 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 study is 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 per cent success rate with skin transplantation," Wu said. Using CRISPR and skin grafts, researchers boost insulin levels to reduce weight.The researchers focused on diabetes because it is a common non-skin disease that can be treated by the strategic delivery of specific proteins. They 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, a tool for precise genetic engineering, they modified the GLP1 gene. They inserted one mutation, designed to extend the hormone's half-life in the blood stream, and fused the modified gene to an antibody fragment so that it would circulate in the blood stream longer.
When these cultured cells were exposed to an air/liquid interface in the laboratory, they stratified, generating a multi-layered, skin-like organoid.Next, they grafted this lab-grown gene-altered skin onto mice with intact immune systems. There was no significant rejection of the transplanted skin grafts.
When the mice ate food containing minute amounts of doxycycline, they released dose-dependent levels of GLP1 into the blood. This promptly increased blood-insulin levels and reduced blood-glucose levels.
When the researchers fed normal or gene-altered mice a high-fat diet, both groups rapidly gained weight. They became obese. When normal and gene-altered mice got the high-fat diet along with varying levels of doxycycline, to induce GLP1 release, the normal mice grew fat and mice expressing GLP1 showed less weight gain.
"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," he said.