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Research Articles, Neurobiology of Disease

Epilepsy gene therapy using an engineered potassium channel

Albert Snowball, Elodie Chabrol, Robert C. Wykes, Tawfeeq Shekh-Ahmad, Jonathan H. Cornford, Andreas Lieb, Michael P. Hughes, Giulia Massaro, Ahad A. Rahim, Kevan S. Hashemi, Dimitri M. Kullmann, Matthew C. Walker and Stephanie Schorge
Journal of Neuroscience 12 February 2019, 1143-18; https://doi.org/10.1523/JNEUROSCI.1143-18.2019
Albert Snowball
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Elodie Chabrol
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Robert C. Wykes
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Tawfeeq Shekh-Ahmad
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Jonathan H. Cornford
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Andreas Lieb
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Michael P. Hughes
2UCL School of Pharmacy, University College London, London WC1N 1AX, UK,
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Giulia Massaro
2UCL School of Pharmacy, University College London, London WC1N 1AX, UK,
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Ahad A. Rahim
2UCL School of Pharmacy, University College London, London WC1N 1AX, UK,
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Kevan S. Hashemi
3Open Source Instruments Inc., Watertown, MA 02472, USA
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Dimitri M. Kullmann
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Matthew C. Walker
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Stephanie Schorge
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
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Abstract

Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon-optimized for human expression and mutated to accelerate the channels' recovery from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a non-integrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled pre-clinical trial, the EKC lentivector robustly reduced seizure frequency in a male rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. When packaged into an adeno-associated viral vector (AAV2/9), the EKC gene was also effective at suppressing seizures in a male rat model of temporal lobe epilepsy. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as ready for clinical translation in the treatment of refractory focal epilepsy.

SIGNIFICANCE STATEMENT

Pharmacoresistant epilepsy affects up to 0.3% of the population. Although epilepsy surgery can be effective it is limited by risks to normal brain function. We have developed a gene therapy that builds on a mechanistic understanding of altered neuronal and circuit excitability in cortical epilepsy. The potassium channel gene KCNA1 was mutated to bypass post-transcriptional editing, and packaged in a non-integrating lentivector to reduce the risk of insertional mutagenesis. A randomized, blinded pre-clinical study demonstrated therapeutic effectiveness in a rodent model of focal neocortical epilepsy. Adeno-associated viral delivery of the channel to both hippocampi was also effective in a model of temporal lobe epilepsy. These results support clinical translation to address a major unmet need.

Footnotes

  • The authors have intellectual property on the use of engineered potassium channels. KSH is the majority share-holder of Open Source Instruments, Inc.

  • We thank G. Schiavo (UCL Institute of Neurology) for the gift of TeNT, S. Hart (UCL Institute of Child Health) for the Neuro-2a cells, and A. J. Thrasher and W. Qasim (UCL Institute of Child Health) for the pMDG-VSV.G and pCMVdR8.74D64V plasmids. We are grateful for the animal care provided by members of our Biological Services Unit. This work was supported by the Medical Research Council, the Wellcome Trust, Epilepsy Research UK, a Marie Skłodowska-Curie Actions Research Fellowship, and a Royal Society University Research Fellowship.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Epilepsy gene therapy using an engineered potassium channel
Albert Snowball, Elodie Chabrol, Robert C. Wykes, Tawfeeq Shekh-Ahmad, Jonathan H. Cornford, Andreas Lieb, Michael P. Hughes, Giulia Massaro, Ahad A. Rahim, Kevan S. Hashemi, Dimitri M. Kullmann, Matthew C. Walker, Stephanie Schorge
Journal of Neuroscience 12 February 2019, 1143-18; DOI: 10.1523/JNEUROSCI.1143-18.2019

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Epilepsy gene therapy using an engineered potassium channel
Albert Snowball, Elodie Chabrol, Robert C. Wykes, Tawfeeq Shekh-Ahmad, Jonathan H. Cornford, Andreas Lieb, Michael P. Hughes, Giulia Massaro, Ahad A. Rahim, Kevan S. Hashemi, Dimitri M. Kullmann, Matthew C. Walker, Stephanie Schorge
Journal of Neuroscience 12 February 2019, 1143-18; DOI: 10.1523/JNEUROSCI.1143-18.2019
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