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

Research output: Contribution to journalArticlepeer-review


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.Weset 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 recovery of the channels from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a nonintegrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled preclinical 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 being ready for clinical translation in the treatment of refractory focal epilepsy.

Original languageAmerican English
Pages (from-to)3159-3169
Number of pages11
JournalJournal of Neuroscience
Issue number16
StatePublished - 17 Apr 2019
Externally publishedYes


  • EEG
  • Epilepsy
  • Gene therapy
  • Lentivirus
  • Potassium channel
  • Seizure detection

All Science Journal Classification (ASJC) codes

  • General Neuroscience


Dive into the research topics of 'Epilepsy gene therapy using an engineered potassium channel'. Together they form a unique fingerprint.

Cite this