Only Hit the Bad Guys: A Gene Therapy Approach to Selectively Silence Highly Active Neurons Reduces Chronic Seizures in Epileptic Mice

On-Demand Cell-Autonomous Gene Therapy for Brain Circuit Disorders Qiu Y, O’Neill N, Maffei B, Zourray C, Almacellas-Barbanoj A, Carpenter JC, Jones SP, Leite M, Turner TJ, Moreira FC, Snowball A, Shekh-Ahmad T, Magloire V, Barral S, Kurian MA, Walker MC, Schorge S, Kullmann DM, Lignani G. Science. 2022;378(6619):523-532. doi:10.1126/science.abq6656. PMID: 36378958; PMCID: PMC7613996 Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and “healthy” surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy. We used an immediate early gene promoter to drive the expression of Kv1.1 potassium channels specifically in hyperactive neurons, and only for as long as they exhibit abnormal activity. Neuronal excitability was reduced by seizure-related activity, leading to a persistent antiepileptic effect without interfering with normal behaviors. Activity-dependent gene therapy is a promising on-demand cell-autonomous treatment for brain circuit disorders.