No FDA-approved treatment exists for cocaine abuse, but for years, researchers have been pinning their hopes on a human enzyme, butyrylcholinesterase, that naturally degrades the drug. The challenge has been making the enzyme work efficiently in a long-lasting way, and now a University of Chicago team says they have an answer.
Led by neurobiologist Ming Xu and skin specialist Xiaoyang Wu, the team engineered skin stem cells taken from newborn animals to produce a turbocharged version of the enzyme. They then grafted the skin back onto the same mice, where it provided a continuous supply of the cocaine-busting protein (Nat. Biomed. Eng. 2018, DOI:10.1038/s41551-018-0293-z). The idea is that if cocaine can be degraded fast enough while in the bloodstream, there won’t be enough left to reach the brain.
Cocaine works by blocking reuptake of the neurotransmitter dopamine. Increased dopamine levels can trigger more movement and more reward-seeking behaviors. But mice grafted with the engineered skin cells rapidly metabolized cocaine, exhibited lower dopamine levels, and had less travel distance in the test chamber, confirming fewer effects on the brain. Moreover, the animals did not develop a preference for the place that was associated with cocaine, suggesting the approach blocked the cocaine-seeking behavior.
While a lethal dose of cocaine killed control animals within minutes, mice with engineered cells acted as if nothing had happened. When the researchers monitored the level of the cocaine-busting enzyme in these mice’s blood, they found it stayed stable for months.
The team’s goal is to do clinical trials and ultimately apply the approach to save lives, Xu says. He also expects the approach to be effective in dealing with alcohol, nicotine, and opioid abuse, as well as abuse of multiple drugs.
But the new strategy isn’t the only approach scientists are trying. Stephen Brimijoin of Mayo Clinic, a neurobiologist who is using viral vectors to deliver similar enzymes in animals (Molecules 2017, DOI:10.3390/molecules22071145), says an approach to treating cocaine abuse using patients’ own skin cells could be “very safe and long lasting,” but more work is needed.
Chang-Guo Zhan at the University of Kentucky, who is not involved in the current study, helped create the fast version of the cocaine-degrading enzyme. His team has reported a therapy in rats which requires only the direct injection of a long-acting version of the protein (Proc. Nat. Acad. Sci. USA 2015, DOI:10.1073/pnas.1517713113). He praised the new approach’s novelty, but cautioned that the blood plasma concentration of the enzyme in the current study might be too low to completely block cocaine-induced physiological effects. “Hopefully, the expression level using this approach can be improved significantly moving forward,” he says.
In response to the comment, Xu says his team’s results demonstrated the amount of the enzyme produced was sufficient to prevent development of cocaine-seeking behavior, cocaine-induced relapse, as well as overdose in mice. “We can use a stronger promoter to drive gene expression if necessary,” he says.