Biochemical autoregulatory gene therapy for focal epilepsy

Despite the introduction of over a dozen new antiepileptic drugs in the last 20 years, approximately one third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies show encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here we describe an autoregulatory anti-epileptic gene therapy, which relies on neuronal inhibition in response to elevations of extracellular glutamate. It is effective in a rodent model of focal epilepsy, and well tolerated, thus lowering the barrier to clinical translation.