The program by Matthijs Verhage (FGA) and long-term collaborator Jakob Sorensen will systematically compare synaptic defects, EEG biomarkers and cognitive deficits between patients and mouse models
Mutations in many genes cause neurodevelopmental disorders, but treatment options are generally very limited. Diversity and overlap in symptoms make it very difficult to stratify patients and design new therapies. This is particularly true for patients carrying mutations in proteins central to both excitatory and inhibitory synaptic communication, STXBP1, SNAP25, STX1B and VAMP2. Mutations typically lead to complex clinical profiles with severe early-onset epilepsy and encephalopathy (EE), intellectual disability (ID) and other comorbidities, including autism. Verhage, long-term collaborator Sorensen and partners from the Danish Filadelphia hospital aim to exploit knowledge from animal models to identify disease mechanisms and improve translation through systematic (side-by-side) comparison to human patient and EEG data, obtained in concert. In addition, stem-cell based in vitro models will be exploited to compare synaptic deficits in humans and compare these to synaptic studies in mouse models. These patient-own cell models will be used in the future as screening platforms for new therapy design.
Central in the program is the hypothesis that mutations in synaptic genes lead to an imbalance in the ratio between excitatory and inhibitory neurotransmission (E/I-ratio), and this imbalance in turn leads to hyperexcitability and Intellectual Disability. Together, this project will not only help to elucidate the basis for EE, but also establish new methods for improved patient stratification, diagnosis and drug discovery.
The Lundbeck project team having fun with vesicles, (partially zippered) SNARE-complexes and Munc18 (green)