Is On-Demand Dynorphin Destined to Be in Demand to Decrease Seizures?

Dynorphin-Based “Release on Demand” Gene Therapy for Drug-Resistant Temporal Lobe Epilepsy Agostinho AS, Mietzsch M, Zangrandi L, et al. EMBO Mol Med. 2019;11(10):e9963. doi:10.15252/emmm.201809963 Focal epilepsy represents one of the most common chronic central nervous system diseases. The high incidence of drug resistance, devastating comorbidities, and insufficient responsiveness to surgery pose unmet medical challenges. In the quest of novel, disease-modifying treatment strategies of neuropeptides represent promising candidates. Here, we provide the “proof of concept” that gene therapy by adeno-associated virus vector transduction of preprodynorphin into the epileptogenic focus of well-accepted mouse and rat models for temporal lobe epilepsy leads to suppression of seizures over months. The debilitating long-term decline of spatial learning and memory is prevented. In human hippocampal slices obtained from epilepsy surgery, dynorphins suppressed seizure-like activity, suggestive of a high potential for clinical translation. Adeno-associated virus delivered preprodynorphin expression is focally and neuronally restricted and release is dependent on high-frequency stimulation, as it occurs at the onset of seizures. The novel format of “release on demand” dynorphin delivery is viewed as a key to prevent habituation and to minimize the risk of adverse effects, leading to long-term suppression of seizures and of their devastating sequel.