Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Gene therapy in epilepsy—is it time for clinical trials?

Nature Reviews Neurology volume 10, pages 300–304 (2014)Cite this article

Subjects

Abstract

Epilepsy represents a major burden to society, not least because approximately 25% of patients do not respond satisfactorily to antiepileptic medication, and only a minority with pharmacoresistant epilepsy are eligible for potentially curative surgery. Several studies have explored gene therapy as a treatment strategy. The translation of scientific breakthroughs into the clinic faces several challenges, including the validation of experimental models of human pharmacoresistant epilepsy, establishment of sensitive and specific measures of therapeutic efficacy, and evaluation of the long-term safety of gene therapy. On the basis of successful reports of gene therapy in experimental models of epilepsy, a roadmap toward clinical trials is proposed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A patient-centred approach to gene therapy for epilepsy.

Similar content being viewed by others

References

  1. Picot, M.-C., Baldy-Moulinier, M., Daurès, J.-P., Dujols, P. & Crespel, A. The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia 49, 1230–1238 (2008).

    Article  Google Scholar 

  2. Kwan, P., Schachter, S. C. & Brodie, M. J. Drug-resistant epilepsy. N. Engl. J. Med. 365, 919–926 (2011).

    Article  CAS  Google Scholar 

  3. Schuele, S. U. & Lüders, H. O. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol. 7, 514–524 (2008).

    Article  Google Scholar 

  4. Kahane, P. & Depaulis, A. Deep brain stimulation in epilepsy: what is next? Curr. Opin. Neurol. 23, 177–182 (2010).

    Article  Google Scholar 

  5. Van Dycke, A., Raedt, R., Vonck, K. & Boon, P. Local delivery strategies in epilepsy: a focus on adenosine. Seizure 20, 376–382 (2011).

    Article  Google Scholar 

  6. Rothman, S. M. The therapeutic potential of focal cooling for neocortical epilepsy. Neurotherapeutics 6, 251–257 (2009).

    Article  Google Scholar 

  7. Sebe, J. Y. & Baraban, S. C. The promise of an interneuron-based cell therapy for epilepsy. Dev. Neurobiol. 71, 107–117 (2011).

    Article  Google Scholar 

  8. Simonato, M. et al. Progress in gene therapy for neurological disorders. Nat. Rev. Neurol. 9, 277–291 (2013).

    Article  CAS  Google Scholar 

  9. Richichi, C. et al. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J. Neurosci. 24, 3051–3059 (2004).

    Article  CAS  Google Scholar 

  10. Noè, F. et al. Neuropeptide Y gene therapy decreases chronic spontaneous seizures in a rat model of temporal lobe epilepsy. Brain 131, 1506–1515 (2008).

    Article  Google Scholar 

  11. Paradiso, B. et al. Localized delivery of fibroblast growth factor-2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model. Proc. Natl Acad. Sci. USA 106, 7191–7196 (2009).

    Article  CAS  Google Scholar 

  12. Haberman, R. P., Samulski, R. J. & McCown, T. J. Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat. Med. 9, 1076–1080 (2003).

    Article  CAS  Google Scholar 

  13. McCown, T. J. Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol. Ther. 14, 63–68 (2006).

    Article  CAS  Google Scholar 

  14. Wykes, R. C. et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci. Transl. Med. 4, 161ra152 (2012).

    Article  Google Scholar 

  15. Kanter-Schlifke, I., Georgievska, B., Kirik, D. & Kokaia, M. Seizure suppression by GDNF gene therapy in animal models of epilepsy. Mol. Ther. 15, 1106–1113 (2007).

    Article  CAS  Google Scholar 

  16. Woldbye, D. P. D. et al. Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures. Brain 133, 2778–2788 (2010).

    Article  Google Scholar 

  17. Paradiso, B. et al. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus. Epilepsia 52, 572–578 (2011).

    Article  Google Scholar 

  18. Bovolenta, R. et al. Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures. J. Neuroinflammation 7, 81 (2010).

    Article  Google Scholar 

  19. Raol, Y. H. et al. Enhancing GABAA receptor α1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy. J. Neurosci. 26, 11342–11346 (2006).

    Article  CAS  Google Scholar 

  20. McClelland, S. et al. Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann. Neurol. 70, 454–464 (2011).

    Article  CAS  Google Scholar 

  21. Jimenez-Mateos, E. M. et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat. Med. 18, 1087–1094 (2012).

    Article  CAS  Google Scholar 

  22. Annegers, J. F., Hauser, W. A., Coan, S. P. & Rocca, W. A. A population-based study of seizures after traumatic brain injuries. N. Engl. J. Med. 338, 20–24 (1998).

    Article  CAS  Google Scholar 

  23. Annegers, J. F., Hauser, W. A., Beghi, E., Nicolosi, A. & Kurland, L. T. The risk of unprovoked seizures after encephalitis and meningitis. Neurology 38, 1407–1410 (1988).

    Article  CAS  Google Scholar 

  24. Burn, J. et al. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ 315, 1582–1587 (1997).

    Article  CAS  Google Scholar 

  25. Galanopoulou, A. S. et al. Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53, 571–582 (2012).

    Article  Google Scholar 

  26. Wilcox, K. S. et al. Issues related to development of new antiseizure treatments. Epilepsia 54 (Suppl. 4), 24–34 (2013).

    Article  Google Scholar 

  27. Bien, C. G. et al. Trends in presurgical evaluation and surgical treatment of epilepsy at one centre from 1988–2009. J. Neurol. Neurosurg. Psychiatr. 84, 54–61 (2013).

    Article  Google Scholar 

  28. De Tisi, J. et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 378, 1388–1395 (2011).

    Article  Google Scholar 

  29. Hermann, B. P., Wyler, A. R., Bush, A. J. & Tabatabai, F. R. Differential effects of left and right anterior temporal lobectomy on verbal learning and memory performance. Epilepsia 33, 289–297 (1992).

    Article  CAS  Google Scholar 

  30. Kelly, K. M. et al. Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats. Epilepsy Res. 47, 189–203 (2001).

    Article  CAS  Google Scholar 

  31. Kharlamov, E. A., Jukkola, P. I., Schmitt, K. L. & Kelly, K. M. Electrobehavioral characteristics of epileptic rats following photothrombotic brain infarction. Epilepsy Res. 56, 185–203 (2003).

    Article  CAS  Google Scholar 

  32. Paz, J. T. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat. Neurosci. 16, 64–70 (2013).

    Article  CAS  Google Scholar 

  33. Whittington, M. A. & Jefferys, J. G. Epileptic activity outlasts disinhibition after intrahippocampal tetanus toxin in the rat. J. Physiol. (Lond.) 481, 593–604 (1994).

    Article  CAS  Google Scholar 

  34. Mellanby, J., George, G., Robinson, A. & Thompson, P. Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus. J. Neurol. Neurosurg. Psychiatr. 40, 404–414 (1977).

    Article  CAS  Google Scholar 

  35. Nilsen, K. E., Walker, M. C. & Cock, H. R. Characterization of the tetanus toxin model of refractory focal neocortical epilepsy in the rat. Epilepsia 46, 179–187 (2005).

    Article  Google Scholar 

  36. Louis, E. D., Williamson, P. D. & Darcey, T. M. Chronic focal epilepsy induced by microinjection of tetanus toxin into the cat motor cortex. Electroencephalogr. Clin. Neurophysiol. 75, 548–557 (1990).

    Article  CAS  Google Scholar 

  37. Hagemann, G., Hoeller, M., Bruehl, C., Lutzenburg, M. & Witte, O. W. Effects of tetanus toxin on functional inhibition after injection in separate cortical areas in rat. Brain Res. 818, 127–134 (1999).

    Article  CAS  Google Scholar 

  38. Mainardi, M., Pietrasanta, M., Vannini, E., Rossetto, O. & Caleo, M. Tetanus neurotoxin-induced epilepsy in mouse visual cortex. Epilepsia 53, e132–e136 (2012).

    Article  Google Scholar 

  39. Kullmann, D. M. Neurological channelopathies. Annu. Rev. Neurosci. 33, 151–172 (2010).

    Article  CAS  Google Scholar 

  40. Lin, E.-J. D., Young, D., Baer, K., Herzog, H. & During, M. J. Differential actions of NPY on seizure modulation via Y1 and Y2 receptors: evidence from receptor knockout mice. Epilepsia 47, 773–780 (2006).

    Article  Google Scholar 

  41. Boison, D. in Jasper's Basic Mechanisms of the Epilepsies (eds Noebels, J. L. et al.) (National Center for Biotechnology Information, 2012).

    Google Scholar 

  42. Haberman, R. et al. Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus vectors, NMDAR1 antisense, and focal seizure sensitivity. Mol. Ther. 6, 495–500 (2002).

    Article  CAS  Google Scholar 

  43. Boison, D. Inhibitory RNA in epilepsy: research tools and therapeutic perspectives. Epilepsia 51, 1659–1668 (2010).

    Article  CAS  Google Scholar 

  44. Mazzuferi, M. et al. Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy. Ann. Neurol. 74, 560–568 (2013).

    Article  CAS  Google Scholar 

  45. Tønnesen, J., Sørensen, A. T., Deisseroth, K., Lundberg, C. & Kokaia, M. Optogenetic control of epileptiform activity. Proc. Natl Acad. Sci. USA 106, 12162–12167 (2009).

    Article  Google Scholar 

  46. Sukhotinsky, I. et al. Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy model. PLoS ONE 8, e62013 (2013).

    Article  CAS  Google Scholar 

  47. Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).

    Article  Google Scholar 

  48. Manfredsson, F. P. & Mandel, R. J. Development of gene therapy for neurological disorders. Discov. Med. 9, 204–211 (2010).

    PubMed  Google Scholar 

  49. Gray, S. J. et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood–brain barrier (BBB). Mol. Ther. 18, 570–578 (2010).

    Article  CAS  Google Scholar 

  50. Abordo-Adesida, E. et al. Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses. Hum. Gene Ther. 16, 741–751 (2005).

    Article  CAS  Google Scholar 

  51. Rodnitzky, R. L. Upcoming treatments in Parkinson's disease, including gene therapy. Parkinsonism Relat. Disord. 18 (Suppl. 1), S37–S40 (2012).

    Article  Google Scholar 

  52. Rahim, A. A. et al. Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors. Gene Ther. 16, 509–520 (2009).

    Article  CAS  Google Scholar 

  53. Bartlett, D. L. et al. Oncolytic viruses as therapeutic cancer vaccines. Mol. Cancer 12, 103 (2013).

    Article  Google Scholar 

  54. Binnie, C. D. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol. 2, 725–730 (2003).

    Article  Google Scholar 

  55. Noebels, J. A perfect storm: converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation. Epilepsia 52 (Suppl. 1), 39–46 (2011).

    Article  Google Scholar 

  56. Mavilio, F. Gene therapies need new development models. Nature 490, 7 (2012).

    Article  CAS  Google Scholar 

  57. Wilson, J. M. Moving to the clinic with gene therapy through our new journal expansion, human gene therapy clinical development. Hum. Gene Ther. 23, 1029–1030 (2012).

    Article  CAS  Google Scholar 

  58. NGVB National Gene Vector Biorepository [online], (2014).

  59. Tremblay, J. P. et al. Translating the genomics revolution: the need for an international gene therapy consortium for monogenic diseases. Mol. Ther. 21, 266–268 (2013).

    Article  CAS  Google Scholar 

  60. Lerchner, W., Corgiat, B., Der Minassian, V., Saunders, R. C. & Richmond, B. J. Injection parameters and virus dependent choice of promoters to improve neuron targeting in the nonhuman primate brain. Gene Ther. http://dx.doi.org/10.1038/gt.2013.75.

Download references

Acknowledgements

Work in the authors' laboratories is supported by the Wellcome Trust, Medical Research Council, European Research Council and the Royal Society.

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Epilepsy, University College London, Institute of Neurology, Queen Square House, Queen Square, London, WC1N 3BG, UK

    Dimitri M. Kullmann, Stephanie Schorge, Matthew C. Walker & Robert C. Wykes

Authors
  1. Dimitri M. Kullmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephanie Schorge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew C. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert C. Wykes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Dimitri M. Kullmann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kullmann, D., Schorge, S., Walker, M. et al. Gene therapy in epilepsy—is it time for clinical trials?. Nat Rev Neurol 10, 300–304 (2014). https://doi.org/10.1038/nrneurol.2014.43

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2014.43

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research