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Gene-Edited Stem Cells Reduce Cocaine Seeking, Overdoses

Cocaine addiction

(National Resource Directory)

18 September 2018. The genome-editing technique Crispr used with stem cells is shown to release enzymes that reduce cocaine-seeking behavior in lab mice and protect against overdoses. A team from University of Chicago describes its techniques in yesterday’s issue of the journal Nature Biomedical Engineering (paid subscription required).

Cocaine is an addictive stimulant made from the coca plant, often abused as a recreational street drug. The drug is sold and inhaled through the nose as a fine powder, injected in the blood stream, or smoked in crystal form, known as crack. Cocaine works in the brain by increasing levels of the neurotransmitter chemical dopamine, and also prevents dopamine from being recycled into nerve cells, allowing the neurotransmitter to accumulate. This build-up of dopamine in the brain provides a sudden reward, or “high,” that reinforces drug-taking behavior, but also desensitizes reward circuits, requiring larger and more frequent doses to maintain the reward.

In addition to physical symptoms (e.g., nausea and irregular heartbeat), as well as unpredictable and violent behavior, increasing cocaine use can lead to overdoses. According to National Institute on Drug Abuse and CDC, the number of cocaine overdose deaths in the U.S. more than doubled since 2012, rising from about 6,000 that year to more than 14,500 in 2017.

University of Chicago researchers, led by medical school professors Ming Xu and Xiaoyang Wu are seeking ways to break cocaine’s addiction cycle. An enzyme in the body known as butyrylcholinesterase or BCHE is known to metabolize and degrade cocaine, and other drugs prone to abuse. The problem with BCHE is it works only briefly in the body, which makes it difficult to use as a treatment for cocaine addiction. The team thus sought a way to extend BCHE’s active time to make it an effective treatment.

In earlier research, Wu and colleagues showed the feasibility of the genome-editing technique Crispr with skin stem cells for insulin production in lab mice that can be grown into cellular collections called organoids and transplanted back to the skin of the animals. Crispr, short for clustered regularly interspaced short palindromic repeats, is a technique for editing genomes based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. Skin grafts and transplants are common therapies to treat burns, for example, and the authors say this stem cell technique is a variation of the practice.

In this case, the Chicago team used Crispr edited the genomes of skin progenitor and stem cells from newborn mice adding a gene to express engineered BCHE enzymes with longer active lifetimes than than the natural form. The researchers cultured the stem cells to transform into skin cells which were transplanted into lab mice induced with cocaine addictions. The transplanted skin cells grew normally and were well tolerated by the mice.

“We had an effective enzyme that can degrade cocaine with high efficiency,” says Xu in a university statement. “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.”

The team reports mice with the engineered BCHE skin transplants were able to clear cocaine from their blood steams faster than untreated mice. As a result, the treated mice showed less drug-seeking behavior, such as entering areas associated with cocaine supplies than untreated mice. Also, the skin-transplant mice withstood overdose quantities of cocaine that the authors say would have killed untreated mice. In addition, expression of  BCHE continued for about 10 weeks in the mice, which suggests the treatments can have longer term effects.

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