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Skin transplantation might be an effective approach to deliver gene therapy to successfully treat type 2 diabetes and obesity, new research in mice suggests.
The technique could enable a wide range of gene-based therapies to treat several human ailments.
“We believe this can supply a long-term safe option for the treatment of several ailments…”
“We solved some technical hurdles and designed a mouse-to-mouse skin transplantation model in animals with intact immune systems,” says study author Xiaoyang Wu, assistant professor in the cancer study department at the University of Chicago.
“We believe this platform has the potential to lead to safe and durable gene therapy in mice and, we expect, in humans, using selected and modified cells.”
Starting in the 1970s, physicians learned how to crop skin stem cells in a patient with extensive burn wounds, develop them in the lab, then employ the lab-grown tissue to close and protect a patient’s wounds. This approach is now normal. On the other hand, the use of skin care is much better developed in humans than in mice.
“The mouse system is not as mature,” Wu says. “It took us a couple of years to optimize our 3D epidermis organoid culture system”
This analysis 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% success rate with skin transplantation,” Wu says. “That is exciting for us.”
The researchers focused on diabetes since it’s a typical non-skin disorder which may be treated by the strategic delivery of particular proteins.
They added the gene for glucagon-like peptide 1 (GLP1), a hormone which stimulates the pancreas to secrete insulin. This excess insulin eliminates excessive glucose in the bloodstream, preventing the complications of diabetes. GLP1 may also delay gastric emptying and decrease appetite.
Using CRISPR, a tool for precise genetic technology, they modified the GLP1 gene. They added one mutation, designed to expand the hormone’s half-life in the blood flow, and fused the modified receptor into an antibody fragment so that it would circulate in the blood stream longer. They also attached an inducible promoter, which enabled them to turn on the gene to make more GLP1, as required, by exposing it to the antibiotic doxycycline. They then added the gene into skin cells and also grew those cells in society.
When these cultured cells have been exposed to an air/liquid interface in the lab they stratified, generating what the writers referred to as a multi-layered, “skin-like organoid.”
Next, they grafted this lab-grown gene-altered skin with intact immune systems. There wasn’t any significant rejection of the transplanted skin grafts.
When the mice ate meals containing minute amounts of doxycycline, they introduced dose-dependent levels of GLP1 into the blood. This immediately increased blood-insulin amounts and reduced blood-glucose levels.
When the investigators fed ordinary or gene-altered mice per high-fat diet, the two groups quickly gained weight. They became obese. When ordinary and gene-altered mice obtained the high-fat diet along with varying amounts of doxycycline, to cause GLP1 launch, the ordinary mice grew obese and mice expressing GLP1 revealed less fat gain.
Expression of GLP1 additionally lowered glucose levels and reduced insulin resistance.
“Collectively, our data strongly suggest that cutaneous gene therapy with inducible expression of GLP1 may be used for the treatment and prevention of diet-induced obesity and pathologies,” the authors write.
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When they transplanted gene-altered cells to mice with a restricted immune system, they saw the same effect. The results, the authors wrote, imply that “cutaneous gene therapy for GLP1 secretion may be both practical and clinically important.”
This approach, combining precise genome editing in vitro with effective use of engineered cells in vivo, can provide “significant gains for treating several human diseases,” the authors note.
“We believe this can supply a long-term safe option for the treatment of several ailments,” Wu says. “It may be used to produce therapeutic proteins, replacing missing proteins for people with a genetic flaw, like hemophilia. Or it might function as a metabolic sink, eliminating various toxins”
Skin progenitor cells have several unique benefits which are an ideal match for gene therapy. Human skin is the biggest and most accessible organ within the body. It’s simple to monitor. Transplanted skin can be quickly removed if necessary. Skins cells rapidly proliferate in culture and can be easily transplanted. The process is safe, minimally invasive, and cheap.
There is also a need. More than 100 million US adults have 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 fat.
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Additional authors of the study are in the University of Chicago and the University of Illinois at Chicago. The National Institutes of Health, the American Cancer Society, along with the V Foundation financed the study.