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 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.

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Fig. 1: Expression of engineered hBChE via genome editing in skin epidermal stem cells.
Fig. 2: Engraftment of hBChE-expressing cells can reduce cocaine-induced locomotion and protect against cocaine overdose.
Fig. 3: Engraftment of hBChE-expressing cells can attenuate CPP acquisition and reinstatement induced by cocaine.
Fig. 4: Expression of hBChE in human epidermal stem cells with CRISPR.

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information. Source data for Figs. 2 and 3 are available in Figshare at https://figshare.com/s/898c3ab26b10a3d08b13.

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Acknowledgements

We are very grateful to L. Becker and X. Zhuang at the University of Chicago, M. Schober at New York University School of Medicine, and E. Fuchs at the Rockefeller University for sharing reagents and technical assistance. We thank L. Degenstein at the transgenic core facility at the University of Chicago for excellent technical assistance. We thank M. Roitman at the University of Illinois at Chicago for advice on dopamine measurements. The animal studies were carried out in the Animal Lovers Against Animal Cruelty-accredited animal research facility at the University of Chicago. This work was supported by grants NIH R01AR063630 and R01OD023700, the Research Scholar Grant (RSG-13-198-01) from the American Cancer Society, and the V Scholar Award from the V Foundation to X.W., and by NIH DA036921, DA043361 and CTSA UL1 TR000430 to M.X.

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X.W. and M.X. designed the experiments. Y.L., Q.K., J.Y. and X.G. performed the experiments. Y.L., Q.K., J.Y., M.X. and X.W. analysed the data. X.W. and M.X. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Ming Xu or Xiaoyang Wu.

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Supplementary Video 1

Behaviour of mice that received GhBChE or GWT 5 min after intraperitoneal injection of 80 mg kg–1 of cocaine.

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Li, Y., Kong, Q., Yue, J. et al. Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose. Nat Biomed Eng 3, 105–113 (2019). https://doi.org/10.1038/s41551-018-0293-z

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