Epilepsy gene therapy using non-integrating lentiviral delivery of an engineered potassium channel gene

Abstract

Refractory focal neocortical 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 rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. 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.

Gentherapien für Epilepsie: Klinische Studien sind auf dem Weg

“…Innerhalb der nächsten Jahre wurde dann die virale Überexpression von K V 1.1 in verschiedenen genetischen und pharmakologischen Epilepsie-Mausmodellen getestet. Hierbei zeigte sich, dass die Tiere nach der Virus-Injektion deutlich weniger Anfälle hatten, auch wenn sie nicht anfallsfrei wurden 13 . Durch mehrere Verfeinerungen, wie etwa dem Einsatz des CAMK2A Promoters, der im Menschen nur in den glutamatergen Pyramidenzellen vorkommt, konnte nun ein K V 1.1 enthaltender Lentivirus für humane Studien generiert werden.…”