Genetic skin grafting helps mice kill cocaine | Science

Addiction to a drug – be it alcohol, tobacco, opioids or illicit drugs, such as cocaine – is a chronic condition that leads to addictive compulsive behavior, difficult or impossible to control.

Long-term use alters the structure of brain regions related to judgment, stress, decision-making and behavior, making it increasingly difficult to ignore cravings.

I am a postdoctoral researcher at the Ming Xu Laboratory at the University of Chicago, where we study addiction, with the goal of finding an effective treatment. In an article in Nature Biomedical Engineering, we describe a new approach, which we developed and tested, that blocks the search for cocaine in mice and protects them from high doses that would otherwise be fatal.

How can gene therapy stop addiction?

A natural enzyme called butyrylcholinesterase, which we abbreviate in BChE, is present in human liver and blood. One of the tasks of this enzyme is to break down or metabolize cocaine into inactive and harmless components. In fact, there is even a mutant human BChE (hBChE), which has been genetically engineered to dramatically accelerate cocaine metabolism. This super mutant enzyme should become a therapy for treating cocaine addiction. However, it is difficult to deliver the active enzyme to injecting drug users and to keep this enzyme functioning in live animals.

So, instead of giving the animals the enzyme, we decided to create skin stem cells that carried the BChE enzyme gene. In this way, the skin cells could make the enzyme themselves and provide the animal.

In our study, we first used the CRISPR gene editing technique to edit mouse stem cells and incorporate the hBChE gene. These modified skin cells produced high and constant levels of the hBChE protein, which they then secreted. Then we cultivated these stem cells in the lab and created a flat layer of skin-like tissue that took a few days to develop.

Once the laboratory skin was finished, we transplanted it to host animals where the cells released significant amounts of hBChE into the blood for more than 10 weeks.

With the genetically modified skin graft releasing hBChE into the bloodstream of host mice, we hypothesized that if the mouse was consuming cocaine, the enzyme would rapidly cut off the drug before triggering the pleasure reaction. addictive in the brain.

"Immunize" against cocaine

Cocaine works by increasing dopamine levels in the brain, which results in feelings of reward and euphoria, which triggers a growing need for drugs.

Animals that received the artificial skin graft were able to eliminate more injected cocaine than control animals. Their brains also had lower levels of dopamine.

In addition, cutaneous grafts of hBChE-producing cells can effectively reduce the rate of fatal overdoses by 50% to zero when animals receive a high dose of life-threatening cocaine. When the animals received a lethal dose, all the control animals died while none of the animals having received the treated skin perished. It was as if the enzyme produced by the skin graft had immunized the mice against an overdose of cocaine.

We then assessed whether hBChE-producing cells could protect against the development of cocaine research. We used trained mice to reveal their preference for cocaine by spending more time in an environment rich in cocaine. Under the same assay and training procedures, normal animals gained a preference for cocaine, while host animals with skin grafting did not exhibit this preference, indicating an hBChE cell transplant effectively blocking the effect of cocaine. reward induced by cocaine. Similarly, a hBChE derived from the skin effectively and specifically disturbs the recurrence of cocaine after 25 days of withdrawal.

To test whether this gene therapy approach will work in humans, we have developed a human skin-like tissue from primary skin stem cells that have been genetically engineered by CRISPR to enable the production of hBChE.

We were encouraged to see that the human epidermal cells manufactured produced large amounts of hBChE in cells grown in the laboratory and in mice. This suggests that the concept of gene therapy of the skin could be effective in treating cocaine abuse and overdose in humans in the future.

Adapting this approach to humans could be a promising way of blocking addiction. But first, we must have sufficient evidence that it works well with little side effects. Similarly, skin cell engineering with the enzymes that degrade alcohol and nicotine could be an effective strategy to combat the addiction and abuse of these two drugs.

This article was originally published on The Conversation.

Qingyao Kong, Postdoctoral Researcher in the Department of Anesthesia and Critical Care of the University of Chicago

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