Models for discovery of targeted therapy in genetic epileptic encephalopathies

Abstract

Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.

Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy

“…These genes have been linked to pathways involved in synaptic transmission, ion channels, transcriptional regulation, DNA damage repair, chromatin remodeling, and metabolism . Pathogenic variants in genes involved in ion channel function represent perhaps one of the most common causes of DEEs, also called channelopathies, and their identification and molecular diagnostic specification in individuals with EE can have important therapeutic implications . Pathogenic variants in genes encoding subunits of voltage‐gated calcium channels (VGCCs), that is, CACNA1A , CACNA2D2 , and CACNA2D1 have been linked to epileptic encephalopathy (EE) and/or ataxia phenotypes [MIM#617106, 108500].…”

WONOEP APPRAISAL: The many facets of epilepsy networks

“…However, much of the success in biomedical research has relied on a reductionist approach in which complex systems are systematically taken apart to examine the individual components. When applied to epilepsy, this approach has resulted in many important discoveries in the domains of genetics, cell biology, membrane excitability, and synaptic function . The promise is that these insights will lead to the development of novel therapeutic strategies that will ultimately improve the quality of life of people with epilepsy.…”

eHealth as a Facilitator of Precision Medicine in Epilepsy

“…Third, the genetic architecture of the condition is complex, with mutations in any of over 30 genes sufficient to cause seizures [3]. Fourth, informative phenotypes exist across multiple experimental models to inform on the physiology of a particular molecular diagnosis [4], and fifth, the nature of the condition makes it amenable to connected health/eHealth solutions [5]. There are already remarkable examples of the application of precision therapeutics in epilepsy, and consolidating critical infrastructure would accelerate discovery and expansion.…”