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Biochemical autoregulatory gene therapy for focal epilepsy


Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation.

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Fig. 1: Mode of action and glutamate sensitivity of eGluCl.
Fig. 2: eGluCl decreases acute chemoconvulsant-induced seizures.
Fig. 3: eGluCl decreases the absolute number of seizures in a model of chronic focal neocortical epilepsy.
Fig. 4: eGluCl treatment has no effect on normal brain function.


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We thank G. Schiavo (UCL Institute of Neurology) for the gift of tetanus toxin and S. Hart (UCL Institute of Child Health) for the mouse Neuro-2a cell line. We are grateful to J. Cornford for assistance with ECoG analysis and to K. Hashemi for help optimizing wireless-transmitter use. This project was supported by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement no. 701411 to A.L.); the Medical Research Council (MR/L01095X/1 to D.M.K., S.S. and M.C.W.); and the Wellcome Trust (095580/Z/11/Z to D.M.K.; 104033/Z/14/Z to D.M.K. and S.S.).

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Authors and Affiliations



A.L. and D.M.K. designed all experiments and drafted the manuscript. A.L. performed in vitro electrophysiology and in vivo experiments. A.L. and Y.Q. designed, performed and analyzed in vivo behavioral experiments. Y.Q., A.L., J.P.H. and C.L.D. performed and analyzed all immunostaining experiments. A.L., Y.Q., J.P.H., C.L.D., M.C.W., S.S. and D.M.K. revised the manuscript.

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Correspondence to Andreas Lieb or Dimitri M. Kullmann.

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The authors declare no competing interests.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4

Reporting Summary

Supplementary Video 1

Representative chemoconvulsant-induced seizure

Supplementary Video 2

Representative seizure in the model of chronic focal neocortical epilepsy

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Lieb, A., Qiu, Y., Dixon, C.L. et al. Biochemical autoregulatory gene therapy for focal epilepsy. Nat Med 24, 1324–1329 (2018).

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