Drug addiction – whether it be alcohol, tobacco, opioids or illicit drugs, such as cocaine – is a chronic disease that causes compulsive drug-seeking behavior that people find difficult or even impossible to control, even if they are aware of the harmful, often deadly consequences.
Long-term use changes the structure of brain regions in relation to assessment, stress, decision-making and behavior, making it increasingly difficult to ignore cravings for drugs.
I am a postdoctoral researcher in the Ming Xu laboratory at the University of Chicago, where we study addiction, with the aim of finding an effective remedy. In a newspaper Nature Biomedical Technology, we describe a new approach, which we have developed and tested, that block the search for cocaine in mice and actually protects them against high doses that would otherwise be fatal.
How can gene therapy stop addiction?
The presence in human liver and blood is a natural enzyme called butyrylcholinesterase, which we abbreviate as BChE. One of the tasks of this enzyme is the breakdown, or metabolization, of cocaine in inactive, harmless components. In fact, there is even a mutant human BChE (hBChE) that was genetically manipulated to greatly accelerate the metabolism of cocaine. This super mutant enzyme is expected to become a therapy for the treatment of cocaine addiction. However, administering the active enzyme to addicts by injection and keeping this enzyme active in live animals is a challenge.
So instead of giving the enzyme to the animals, we decided to engineer skin stem cells that carried the gene for the BChE enzyme. In this way, the skin cells could produce the enzyme itself and deliver it to the animal.
In our study we first used the genetic processing method CRISPR to process the mouse skin stem cells and to incorporate the hBChE gene. These engineered skin cells produced consistent and high levels of the hBChE protein, which they then secreted. Then we cultivated these engineered stem cells in the laboratory and created a flat layer of skin-like tissue that took a few days to grow.
After the skin cultured in the laboratory was complete, we transplanted it into host animals where the cells released significant amounts of hBChE in the blood for more than 10 weeks.
With the genetically engineered skin graft that releases hBChE into the blood stream of the host mice, we hypothesized that if the mouse used cocaine, the enzyme would rapidly shred the drug before it could cause the addictive pleasure reaction in the brain.
& # 39; Immunize & # 39; against cocaine
Cocaine works by increasing dopamine levels in the brain, which then result in feelings of reward and euphoria, which trigger a desire for more of the drug.
The animals receiving the engineered skin graft were able to remove injected amounts of cocaine faster than control animals. Their brains also had lower levels of dopamine.
In addition, the skin grafts of hBChE-producing cells can effectively reduce the rate of lethal overdoses from 50% to zero when the animals were injected with a high, possibly lethal, dose of cocaine. When animals received a lethal dose, all control animals died while none of the animals receiving the manipulated skin died. It was as if the enzyme produced by the skin graft had immunized the mice against an overdose of cocaine.
We then investigated whether hBChE-producing cells can protect against the development of cocaine search. We used mice that had been trained to reveal their preference for cocaine by spending more time in a cocaine-rich environment. Under the same dosage and training procedures, normal animals were preferred for cocaine, while host animals with the skin graft were not as preferred, indicating that skin grafting of the hBChE cells efficiently blocks the cocaine-induced reward effect. Similarly, skin-derived hBChE interferes with efficient and specific recurrence of cocaine search after 25 days of withdrawal.
To test whether this gene therapy approach will work in humans, we have grown human skin-like tissue from primary skin stem cells that have been genetically engineered by CRISPR to enable hBChE production.
We were encouraged to see that engineered human epidermal cells produced large amounts of hBChE in cells grown in the laboratory and in mice. This suggests that the concept of skin gene therapy can be effective for treating cocaine abuse and overdose in people in the future.
Adapting this approach to people could be a promising way to block addiction. But first we have to have enough evidence that it works well with few side effects. Similarly, technical skin cells with the enzymes that break down alcohol and nicotine can be an effective strategy to curb addiction and abuse of these two drugs.
This article has been republished in The Conversation under a Creative Commons license. Read the original article.