By the skin of their addiction

Research team finds that skin grafts protect mice from lethal cocaine doses

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CHICAGO—With the rising threat of an opioid addiction epidemic and the potential loss of life as a result of overdoses, it was welcome news when the opioid receptor antagonist medication naloxone arrived on the scene, able to eliminate opioid intoxication to reverse an overdose. But for cocaine, there remains not only no cure for addiction to the drug, but also no approved method to thwart the lethality of an overdose.
And, of course, with cocaine users inevitably becoming less sensitive to the drug and requiring larger and stronger doses—or relapsing after a long period and overwhelming their bodies with a sudden influx of the drug—such remedies are eagerly sought.
A research team at the University of Chicago led by Dr. Ming Xu, a professor of anesthesia and critical care, and Dr. Xiaoyang Wu, an assistant professor in the Ben May Department for Cancer Research, thinks it may have a novel approach for future human use based on testing in mice—one that involves skin grafts.
In the research—published Sept. 17 as “Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose” in Nature Biomedical Engineering—the team was able to suppress the desire for cocaine and also protect against an overdose by genetically editing a patch of normal skin to add an anti-cocaine gene into skin stem cells, and then grafting that skin onto the mice.
The treated mice were less likely than untreated mice to enter environments previously associated with cocaine use; mice exposed to alcohol, however, retained a learned fondness for that drug, notes an article on the University of Chicago website about the research. Interestingly, the method also prevented the death of mice exposed to uniformly lethal doses of cocaine.
“Our study demonstrates that transplantation of genome-edited skin stem cells can be used to deliver an active cocaine hydrolase long-term in vivo,” the authors wrote, adding that they were able to show that epidermal stem cells “can be successfully employed for ex-vivo gene therapy, as efficient genetic manipulation is possible with minimal risk.”
“We had an effective enzyme that can degrade cocaine with high efficiency,” noted Ming Xu. “We had CRISPR, a genetic tool that enabled us to introduce a gene of interest inside the cell without affecting other genes. And, most importantly we had technology, developed by my colleague Xiaoyang Wu, to put genetically modified skin cells back into an immunocompetent recipient. That saved us a lot of trouble.”
The enzyme in question is butyrylcholinesterase (BChE), which can degrade cocaine. The problem is that it has a short half-life, and thus injecting it into muscle tissue is very limited in its efficacy. This inspired the genetic engineering to use primary epidermal basal progenitor/stem cells they had collected from newborn mice as a means to deliver engineered human BChE to the cells. The skin-derived expression of hBChE in host mice with intact immune systems was stable for more than 10 weeks without significant decrease in hBChE.
The oldest mice in this study are now 12 months old and healthy, the authors note, which they say speaks positively for the feasibility of such cutaneous gene therapy, adding: “Taken together, our results show promise of cutaneous gene therapy as a safe and cost-effective therapeutic option for cocaine abuse in the future.” They note that for cocaine addicts or those prone to cocaine abuse, such a method could both reduce drug-seeking behavior and protect against cocaine overdose to make them “immune” to further cocaine abuse.
The researchers also believe the skin cell-based approach could have potential against alcohol, nicotine and opioid abuse as well.
This research news comes a little more than a year since the University of Chicago reported on research by Wu and colleagues (also conducted in mice) to use skin transplants to treat two related and extremely common human ailments: type 2 diabetes and obesity.
The researchers focused on diabetes because it is a common non-skin disease that can be treated by the strategic delivery of specific proteins and, in a strategy not unlike the cocaine protection approach, 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.

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