Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose

Abstract

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 behavioral 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 by 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 hydrolyzes cocaine, enables the long-term release of the enzyme and efficiently protects the mice from cocaine-seeking behavior and cocaine overdose. Cutaneous gene therapy through skin transplants that elicit drug elimination may offer a therapeutic option to address drug abuse.

Change the genes to fix the skin

“…Wu's team has now used this technique to create similar patches of CRISPR-modified skin cells that produce a tweaked version of an enzyme called BChE, which breaks down cocaine 5 . Wu's version metabolizes the drug more than 4,000 times faster than the naturally occurring form, rapidly clearing it from the body and quickly killing the 'high' .…”

Grafting a Safeguard against Cocaine Abuse

“…Moreover, there are no interventions for the acute emergencies that result from cocaine overdose. A novel skin stem cell-based gene therapy has recently been described to be effective in reducing core features of cocaine abuse in laboratory mice [2], offering hope of producing the first medication for treating cocaine abuse, and adding a new tool for treating drug abuse and co-abuse.…”

“…The third and perhaps the most important advance is that Wu and colleagues developed a method for preparation of mouse skin organoid culture and engraftment of the cultured mouse skin substitute to the immunocompetent host mice [2,9]. The epidermal progenitor cells of the skin have several major and unique advantages making them particularly suited for gene therapy ex vivo: i) skin is the most accessible organ in the body, offering availability for collection of epidermal progenitor cells with well-established procedures.…”

“…To address the urgent need to develop a long-lasting treatment of drug abuse, the Wu and Xu labs teamed up and tested whether a skin-based platform for longterm delivery of genes may provide a safeguard against and effective way of treating drug abuse in mice. They found that, upon targeting an hBChE gene into epidermal progenitor cells and grafting the engineered cells, the transgene products can be produced in vivo and can efficiently protect mice from cocaine-seeking behavior including acquisition and relapse, and cocaine overdose [2]. The approach is specific in protecting against cocaine abuse, and not abuse for methamphetamine and alcohol.…”

“…The approach is specific in protecting against cocaine abuse, and not abuse for methamphetamine and alcohol. Not surprisingly, expression of BChE in grafted mice removes cocaine much more quickly in vivo, leading to reduced extracellular DA and locomotor activity [2]. The implications of these results are potentially significant: i) cutaneous gene therapy through skin transplants that elicits drug elimination may offer a therapeutic option to address cocaine abuse, including reducing ongoing and continuous use, relapse induced by drugs, and lethality in users and addicts seeking help or treatment.…”