While the development of the CRISPR gene editing system is turning into one of the biggest scientific breakthroughs of the century, there are still many hurdles to overcome before the technology is efficiently applied in people. One big problem is finding a way to clinically deliver the technology to humans and animals. A University of Chicago team recently overcame this challenge by transplanting CRISPR-treated skin grafts onto mice and showing it to be an effective way to deliver gene therapy to treat diabetes.
Building on 40 years of skin transplant knowledge, the team looked at ways to genetically modify epidermal progenitor cells to see if they could be transplanted into an organism and deliver a targeted gene therapy. To test the process diabetes was chosen as the target illness as it can be treated through strategically delivered proteins.
The team first looked at altering a gene for glucagon-like peptide 1 (GLP1), which is a hormone that is key to many diabetes treatments as it is responsible for stimulating the pancreas to create insulin. The hormone is known to have a very short half-life, so the team initially modified the GLP1 gene using CRISPR and attached it to an antibody fragment to both extend the hormone's half-life in the blood stream and allow the modified gene to circulate in the blood stream longer.
They then attached what is called an inducible promoter to the modified gene. This acts like a switch that causes the gene to produce more GLP1 as needed. In this instance the gene produces more GLP1 when exposed to tiny amounts of the antibiotic doxycycline.
The CRISPR-modified gene was then inserted into skin cells that were grown in a laboratory and ultimately transplanted onto mice. These mice had fully intact immune systems yet no significant rejection of the skin was observed.
The experiment proved a success, with insulin levels of the animals increasing when fed food with minute amounts of doxycycline. Expression of GLP1 was also found to be stable in the animal's bloodstream for more than three months, suggesting long-term benefits from the technique.
While these initial experiments target diabetes, there are plenty of other diseases this technique using genetically engineered skin transplants could be easily applied to.
"We think this can provide a long-term safe option for the treatment of many diseases," says study author Xiaoyang Wu. "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."
In fact, skin cell transplants look to be an ideal way to deliver gene therapy. Skin cultures have shown to be easy to transplant, and removed quickly if necessary. A skin transplant is also safe, inexpensive, and easy to monitor.
While many type 2 diabetics will probably find it easier to manage their illness without having a 20 x 20 cm skin graft that requires their food to be occasionally dosed with an antibiotic trigger, the research is a promising proof-of-concept. The team has demonstrated that skin transplants are not only an efficient way to deliver gene therapy, but that the process can be effectively triggered by an external chemical source.
The research was published in the journal Cell Stem Cell.