Recent advances in gene therapy for neurodevelopmental disorders with epilepsy

Abstract

Neurodevelopmental disorders can be caused by mutations in neuronal genes fundamental to brain development. These disorders have severe symptoms ranging from intellectually disability, social and cognitive impairments, and a subset are strongly linked with epilepsy. In this review, we focus on those neurodevelopmental disorders that are frequently characterized by the presence of epilepsy (NDD + E). We loosely group the genes linked to NDD + E with different neuronal functions: transcriptional regulation, intrinsic excitability and synaptic transmission. All these genes have in common a pivotal role in defining the brain architecture and function during early development, and when their function is altered, symptoms can present in the first stages of human life. The relationship with epilepsy is complex. In some NDD + E, epilepsy is a comorbidity and in others seizures appear to be the main cause of the pathology, suggesting that either structural changes (NDD) or neuronal communication (E) can lead to these disorders. Furthermore, grouping the genes that cause NDD + E, we review the uses and limitations of current models of the different disorders, and how different gene therapy strategies are being developed to treat them. We highlight where gene replacement may not be a treatment option, and where innovative therapeutic tools, such as CRISPR-based gene editing, and new avenues of delivery are required. In general this group of genetically defined disorders, supported increasing knowledge of the mechanisms leading to neurological dysfunction serve as an excellent collection for illustrating the translational potential of gene therapy, including newly emerging tools.

Keywords: disease models; epilepsy; gene therapy; ion channels; neurodevelopmental; synaptic proteins.

Figure 1

Mutated genes in NDD + E. Gene names are drawn where their encoded proteins function in the cell body (A), axon initial segment (B), pre‐synaptic (C) and post‐synaptic (D) terminals. In (A), genes outside the neuron represent ubiquitous expression. In (B), gradient expression of SCN channels is indicated by different font sizes

Figure 2

Potential gene therapy approaches for NDD + E. The onset of the disease is drawn in the early childhood but can vary among the different NDD + E