RT Journal Article
SR Electronic
T1 Epilepsy Gene Therapy Using an Engineered Potassium Channel
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3159
OP 3169
DO 10.1523/JNEUROSCI.1143-18.2019
VO 39
IS 16
A1 Albert Snowball
A1 Elodie Chabrol
A1 Robert C. Wykes
A1 Tawfeeq Shekh-Ahmad
A1 Jonathan H. Cornford
A1 Andreas Lieb
A1 Michael P. Hughes
A1 Giulia Massaro
A1 Ahad A. Rahim
A1 Kevan S. Hashemi
A1 Dimitri M. Kullmann
A1 Matthew C. Walker
A1 Stephanie Schorge
YR 2019
UL http://www.jneurosci.org/content/39/16/3159.abstract
AB 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 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.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 was packaged in a nonintegrating lentivector to reduce the risk of insertional mutagenesis. A randomized, blinded preclinical 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.