A Closer Look...
Development of Genetically Modified Skin Graft for Treating Substance Use Disorder and Polysubstance Abuse
Cocaine addiction is associated with compulsive drug seeking, and exposure to the drug or to drug-associated cues leads to relapse, even after long periods of abstention. A variety of pharmacological targets and behavioural interventions have been explored to counteract cocaine addiction, but to date no market-approved medications for treating cocaine addiction or relapse exist, and effective interventions for acute emergencies resulting from cocaine overdose are lacking. We recently demonstrated that skin epidermal stem cells can be readily edited using CRISPR (clustered regularly interspaced short palindromic repeats) and then transplanted back into the donor mice. Here, we show that the transplantation, into mice, of skin cells modified to express an enhanced form of butyrylcholinesterase—an enzyme that hydrolyses cocaine—enables the long-term release of the enzyme and efficiently protects the mice from cocaine-seeking behaviour and cocaine overdose. Cutaneous gene therapy through skin transplants that elicit drug elimination may offer a therapeutic option to address drug abuse.
Alcohol use disorder (AUD) is one of the foremost public health problems. Alcohol is also frequently co-abused with cocaine. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse. We recently demonstrated that skin grafts generated from mouse epidermal stem cells that had been engineered by CRISPR-mediated genome editing could be transplanted onto mice as a gene delivery platform. Here, we show that expression of the glucagon-like peptide-1 (GLP1) gene delivered by epidermal stem cells attenuated development and reinstatement of alcohol-induced drug-taking and seeking as well as voluntary oral alcohol consumption. GLP1 derived from the skin grafts decreased alcohol-induced increase in dopamine levels in the nucleus accumbens. In exploring the potential of this platform in reducing concurrent use of drugs, we developed a novel co-grafting procedure for both modified human butyrylcholinesterase (hBChE)- and GLP1-expressing cells. Epidermal stem cell-derived hBChE and GLP1 reduced acquisition of drug-taking and toxicity induced by alcohol and cocaine co-administration. These results imply that cutaneous gene delivery through skin transplants may add a new option to treat drug abuse and co-abuse.
Mentions in the News
Our research and lab members have been featured in numerous publications, from the local Hyde Park Herald to the international Wall Street Journal
“…Stem cell researchers at the University of Chicago believe we could be close to a future without drug addiction after recent progress on a revolutionary new treatment…”
“… This system allows Xu and Wu to take a small section of skin, add the anti-cocaine gene to the skin’s cells, and then put it back onto the patient through a process called grafting, a routine procedure where a piece of skin is added onto the body.
The genetically-modified cells produce anti-cocaine proteins that enter the bloodstream and break down cocaine in a way that makes it unrewarding and nontoxic to the brain and body. And because the tool uses a routine skin grafting procedure, the process is safe, minimally invasive, and affordable…”
“Alexis accepted a position at … the Ming Xu Laboratory at her university, where she will help test a novel skin stem-cell treatment for cocaine overdoses on mice…”