Dynorphin‐based “release on demand” gene therapy for drug‐resistant temporal lobe epilepsy

Abstract

Focal epilepsy represents one of the most common chronic CNS 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 (AAV) 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. AAV‐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.

Homeostatic Plasticity in Epilepsy

“…Gene therapy for epilepsy is a promising approach to treat the chronic phase of the pathology (Kullmann et al, 2014). Recent gene therapies target the symptoms (seizures) rather than the cause of epilepsy, for example, decreasing the excitability of excitatory neurons or potentiating inhibitory tone (Richichi et al, 2004;Noè et al, 2008;Wykes et al, 2012;Krook-Magnuson et al, 2013;Kätzel et al, 2014;Lieb et al, 2018;Agostinho et al, 2019;Wickham et al, 2019;Colasante et al, 2020). These therapies have been efficient in decreasing intrinsic neuronal excitability, synaptic transmission, and the number of seizures, in rescuing cognitive defects and also FIGURE 1 | Graphical representation of the potential role of homeostatic plasticity in the epileptic process.…”

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

“… 4 In this work, Agostinho et al explored this prospect using the dynorphin system as a test case in preclinical models of TLE. 5 …”

Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

“…Gene therapy for epilepsy has been performed as preclinical studies on rodent models chiefly targeting focal epilepsy such as temporal lobe epilepsy by local injection of viral vectors. Local induction of preprodynorphin, glutamate‐gated chrolide channel, neuropeptide Y and Y2, voltage‐gated potassium channel, and collybistin, etc., have demonstrated positive outcomes of vector‐mediated gene therapy for epilepsy 14–19 . We also have demonstrated that AAV8 vector‐mediated gene delivery of glutamic acid decarboxylase ( GAD ), a rate‐limiting enzyme for synthesizing inhibitory neuronal transmitter GABA, into the hippocampus of epileptic (EL) mice reduces seizure frequency and strength, but not seizure duration of tonic–clonic convulsion 18 .…”