Gene Editing Makes Mice Cocaine-Proof
Cocaine is one of the most addictive recreational drugs, and the way in which it compels users to seek out more highs is one of the key reasons behind its worldwide use.
A new paper published online this week in Nature Biomedical Engineering has taken a rather unusual route towards treating cocaine addiction – by developing CRISPR-powered skin grafts that produce an anti-cocaine enzyme.
Over 14,000 deaths in the US involved cocaine last year, yet methods to deal with abuse of the drug have so far proved ineffective, both in stopping long-term compulsive cocaine usage, and to prevent death from overdose.
One technique that was once thought promising is the intramuscular injection of modified butyrylcholinesterase (BChE), an enzyme that naturally breaks down cocaine. Protein engineering has created a version of BChE that is 4400 times more effective at breaking down cocaine than the natural enzyme. However, in animal models, the modified enzyme’s short half-life means it disappears before it can have any long-term effects on the body’s response to the drug. Additionally, the drug can’t be administered orally, further reducing its value as a long-term solution for recovering addicts.
What researchers led by Ming Xu and Xiaoyang Wu at the University of Chicago wanted to develop was a way of continuously exposing the body to BChE over time. The team’s ace in the hole was their previously developed CRISPR-based gene-editing platform for modifying the DNA of skin stem cells. Skin cells have been shown to be capable of secreting therapeutic molecules into the bloodstream, such as blood clotting proteins Factor VIII and Factor IX.
Using mice as an animal model (rodents are very much not immune to the temptation of cocaine and have been shown to prefer getting high over, say, eating) the team removed skin cells and engineered them to secrete human BChE, before grafting the cells back under the skin of the same mouse they were taken from. The secreted BChE, according to the study, remained in the animals’ bloodstreams for over 10 weeks, and no rejection of the grafts were seen for months after transplantation.
After having the anti-cocaine cells transplanted, these straight-edge mice proved less keen to seek out cocaine and, amazingly, proved immune to cocaine overdoses that killed mice that had been grafted with non-edited cells.
But what good are cocaine-proof mice, apart from perhaps as a plot device in a new series of Narcos?
The authors suggest that the treatment has potential for treating drug addicts. As the enzyme is highly efficient at breaking down cocaine, it should be able prevent the effects of a wide range of potential doses with little user-to-user variation. The researchers even raise the possibility at the end of their paper of using the same gene editing platform to treat other forms of addiction, such as to alcohol and nicotine – for these, the researchers hope to use a protein called glucagon-like peptide 1, which has been shown to correct diet-induced obesity and diabetes in mice.
Such promising work shows that gene-editing techniques have applications across the entirety of medical science, but as a proof-of-concept study, there is still a long way to go before slap-on anti-cocaine skin grafts are considered feasible and safe for use in humans. Furthermore, the authors note that no amount of gene therapy can stop the environmental cues of drug addiction. In combating this aspect of drug abuse, biology can’t go it alone.