The recent success of first central nervous system gene therapies has reinvigorated the growing community of gene therapy researchers and strengthened the field's market position. We are witnessing an increase of clinical trials with long-term efficiency mainly for neurometabolic, neurodegenerative and neurodevelopmental diseases caused by loss-of-function mutations. The ever-expanding knowledge and accessibility to the most advanced tools allow enrichment of applications to more complex diseases. This gradually contributes towards sealing the gap between top diseases impacting current global health and those towards which gene therapy development is currently aimed. Here, we highlight innovative therapeutic approaches that have reached the clinics and outline the latest improvements of vector design and targeting. Finally, we address the pressing challenges faced by clinical trials and the direction they are heading.

Focal Cortical Dysplasias (FCDs) are a common subtype of malformation of cortical development, which frequently present with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. FCD type II is typically caused by somatic mutations resulting in mTOR hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe FCD. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established FCD model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human RHEB plasmid, an activator of mTOR Complex 1. First, we further characterised this by quantifying electrocorticograms and behavioural abnormalities, both in mice developing spontaneous generalised seizures and in mice only exhibiting abnormal interictal discharges. Then, using continuous video-electrocorticogram recordings from epileptic mice before and after injection of AAV9-CAMK2A-EKC in the dysplastic region, we observed a robust decrease in the frequency of seizures and in interictal activity, compared to mice injected with a control viral vector. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal activity or behaviour in non-epileptic mice. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

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