Circuit-Remodelling Gene Therapy for Brain Circuit Disorders
Gabriele Lignani
Professor of Translational Neuroscience
Research Department of Epilepsy – University College London

Abstract
Several neurodevelopmental and neuropsychiatric disorders, including epilepsy, are characterised by recurrent episodes of pathological network activity. While classical gene therapy aims to correct underlying genetic defects, many brain circuit disorders lack a clear aetiology. Moreover, existing genetic approaches that modulate neuronal excitability cannot distinguish between neurons driving pathological activity and surrounding healthy cells. We developed an activity-dependent gene therapy strategy that selectively downregulates the excitability of overactive neurons in a closed-loop, cell-autonomous manner. We tested this approach across both acquired and genetic models of epilepsy. Neuronal excitability was reduced specifically in response to epilepsy-associated activity, resulting in sustained seizure suppression without impairing normal behaviour in adult animals. Strikingly, when applied early in development in a model of severe epileptic encephalopathy, prior to seizure onset, this therapy prevented the emergence of pathological network formation.
This circuit-remodelling approach has the potential to be applied across diverse forms of epilepsy, irrespective of aetiology. Activity-dependent gene therapy therefore represents a promising on-demand treatment paradigm for brain circuit disorders.

Invited by Jean-Bernard Manent
Monday, September 28th at 2 pm – INMED conference room