Skin gene therapy protects mice against lethal doses of cocaine

There are no drugs approved to treat cocaine addiction or overdose. Frequent users tend to become less and less sensitive to the drug, resulting in higher or more frequent doses. The typical result is dependence. Exposure to drug or drug-related clues, even after long periods of abstention, often results in a relapse.

In the September 17, 2018 issue of Nature Biomedical Engineering, a research team from the University of Chicago led by Ming Xu, Ph.D., professor of anesthesia and intensive care, and Xiaoyang Wu, Ph.D., assistant professor at Ben's Department of Cancer Research May, describe an innovative approach. able to quell the craving for cocaine and protect against overdose – when it is tested in mice.

According to Xu, researchers had three essential mechanisms for treating overdoses and preventing addiction.

"We had an effective enzyme that can degrade cocaine with high efficiency," he said. "We had CRISPR, a genetic tool that allowed us to introduce an interesting gene into the cell without affecting other genes, and most importantly, the technology developed by my colleague Xiaoyang Wu to reinject genetically engineered cells into an immunocompetent recipient. It saved us a lot of problems. "

The enzyme butyrylcholinesterase (BChE) can degrade cocaine. But because of its short half-life, direct injection of BChE into muscle tissue has a profoundly limited effect.

To make long-lasting BChE, the authors collected primary epidermal basal cell / progenitor cells from newborn mice. They used CRISPR to administer manipulated human BChE to the cells.

Then, they used a technique developed by Wu to prepare cutaneous organelles and transplant them into donor animals, where they act as a deposit for robust expression and secretion of hBChE into the bloodstream. This effectively protected mice against relapse caused by cocaine and cocaine. It even prevented the death of mice exposed to uniformly lethal doses of cocaine.

Cutaneous gene therapy can be used as a "safe and effective way to treat non-skin diseases, including drug addiction, a scenario that has not been explored yet," the authors note. "We have demonstrated key evidence that artificial skin grafts can effectively deliver HBChE in vivo and protect against cocaine research and overdose."

These stem cells were well tolerated by the injected mice. The grafted skin cells exhibited normal epidermal stratification, proliferation, and cell death.

Mice that received these skin grafts were able to eliminate cocaine from the bloodstream much faster than normal mice. They were able to resist overdoses of cocaine that would be fatal for 100% of unprotected mice.

Treated mice were less likely than untreated mice to enter environments previously associated with cocaine use. Mice exposed to alcohol, however, retain a penchant for this drug.

"Our study demonstrates that genetically modified skin stem cell transplantation can be used to deliver long-term active cocaine hydrolase in vivo," the authors conclude. They have shown that epidermal stem cells "can be used successfully for gene therapy ex vivo because effective genetic manipulation is possible with minimal risk".

Transplantation protocols have been used clinically for decades in the treatment of burn wounds, as well as genetic disorders of vitiligo and skin, the authors note. These regenerated skin grafts "are stable and have proven their long-term survival".

The dermal expression of hBChE in host mice whose immune system is intact was stable for more than 10 weeks with no significant decrease in hBChE. This suggests that the skin environment may limit any potential immune response to HBChE.

The oldest mice in this study are now 12 months old and in good health, the authors note, confirming the feasibility of cutaneous gene therapy. "Taken together, our results show that cutaneous gene therapy is a safe and cost-effective therapeutic option for cocaine abuse in the future."

For cocaine users or those who are prone to cocaine abuse, this approach could reduce the use of drugs and protect against overdose of cocaine, potentially making them "immune" to cocaine use. This skin cell-based approach can potentially be used to treat the abuse and co-abuse of alcohol, nicotine and opioids.

Creative thinking about cocaine addiction and overdoses is needed. According to the 2015 National Survey on Drug Use and Health, about five percent of young adults in the United States (1.7 million people aged 18 to 25) have used cocaine at least Once. More than 900,000 Americans are addicted to or abuse this popular but illegal drug.

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More information:
Yuanyuan Li et al, epidermal skin stem cells published by the genome protect mice against cocaine-seeking behavior and overdose of cocaine, Nature Biomedical Engineering (2018). DOI: 10.1038 / s41551-018-0293-z