Models for discovery of targeted therapy in genetic epileptic encephalopathies

• Published in: Journal of neurochemistry 2017-10, Vol.143 (1), p.30-48
• Main Authors: Maljevic, Snezana, Reid, Christopher A., Petrou, Steven
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies, Monoclonal - administration & dosage; Anticonvulsants - administration & dosage; Brain Diseases - epidemiology; Brain Diseases - genetics; Brain Diseases - therapy; Cell- and Tissue-Based Therapy - trends; disease models; Disease Models, Animal; Disorders; Drug Delivery Systems - trends; Encephalopathy; Epilepsy; Epilepsy - epidemiology; Epilepsy - genetics; Epilepsy - therapy; Excitatory Amino Acid Antagonists - administration & dosage; Gene sequencing; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Genetic Predisposition to Disease - prevention & control; Genetic Therapy - trends; Genomes; Humans; induced pluripotent stem cells; Ion channels; Molecular modelling; Movement disorders; Precision medicine; Seizures; Stem cells; Therapy
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14134

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. We review the potential for the development of targeted therapies for the genetic epileptic encephalopathies, severe early onset syndromes presenting with refractory seizures and developmental delay. Using the example of ion channels, we address the available and emerging experimental models and how they can identify specific molecular and cellular targets for the novel disease‐based treatments of severely affected patients.