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Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders

Periodic Reporting for period 1 - COSYN (Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders)

Reporting period: 2016-01-01 to 2017-06-30

COSYN is an integrated, state-of-art, bench-to-bedside programme focused on personalised therapeutics. COSYN has integrated outstanding European academic and two large Pharma partners to exploit genomic findings for intellectual disability (ID), autism (ASD), and schizophrenia (SCZ). We capitalize on comorbidity, from clinic to cells and synapses to help understanding these disorders.
We have exploited our access to large existing patient DNA samples across the EU and selected rare genetic variants of strong effect in patients with clinical comorbidity, 10 for 22q11 deletions and 10 for intellectual disability (ID). In Work package 1 (WP1), our clinical COSYN partners have analysed all aspects of comorbidity in the clinical profiles to select these cases, not only the diagnosis of the three main disease classes (ID, ASD, SCZ), but also ID severity, psychosis, epilepsy, other psychiatric features (ADHD, depression, panic disorder), other behavioural problems, dysmosphisms, other medical diagnoses and functional data (MRI and EEG). In addition, the inheritance status and predicted impact of the rare variants are analyzed and queries are performed to find similar cases in other cohorts worldwide. Finally, practical considerations are taken into account to select the 10 most suitable cases for follow-up studies in COSYN, e.g. novelty of the mutation, is the mutated gene expressed in our cellular model system (cortical excitatory neurons), is the predicted effect expected to be cell autonomous and how well are compounds predicted to engage with the gene-product (‘drug-ability’). Using these criteria, the 10 most suitable cases have been selected, our clinical teams have visited these patients and skin biopsies have been taken. Nineteen of these 20 samples are currently available for cellular studies within COSYN (10 cases for 22q11 and 9 for ID). Ten further cases will be selected for ASD, and 10 for SCZ along the same lines in the coming years.
Using these samples as a starting point, we have set out to understand comorbidity by comparing symptom and syndrome overlap with novel neurobiological criteria and to elucidate mechanisms of comorbidity using neurobiology for the major genomic clue of synaptic dysfunction to unravel the cellular mechanisms of comorbidity.
We have generated novel neuronal cell models by using micro-lithography to generate micro-islands of support cells (glia cells) to allow single neurons to grow and form synapses onto themselves in culture (autapses, see figure). We have optimized and characterized these cultures in terms of in vitro maturation and synapse formation. Many in vitro differentiation and maturation procedures have been compared to find the optimal in vitro model and be able to generate novel neurobiological criteria and to elucidate mechanisms of comorbidity using these criteria. We have used patch clamp physiology to characterize synapse maturation and function in vitro and to standardize procedures of systematic analysis of synapses from the selected patients. Furthermore, we have introduced modern genome editing (CRISPR/Cas9) to correct genetic variants in the patient cell lines or to (re-)create the same mutations in a standard (non-patient) cell line. We have established a quality control pipe-line with exome sequencing of all patient in vitro cell lines to identify any confounding genetic rearrangements that regularly emerge during re-programming of the primary (skin) cells and gene editing. Only cell models that pass the stringent QC (approximately 50%) are used for cellular analysis. These novel cellular models provide unique opportunities to discover synaptic deficits associated with these rare genetic variants of strong effect and to build future cell models for compound screening and therapy design. In addition to these novel models, COSYN also exploits conventional cell culture models for high content screening (cellomics) and synapse recordings.
The consortium has already generated the first 10 patient lines for 22q11 deletions. Ten additional lines for intellectual disability are currently being processed and autism and schizophrenia cases will follow. In all these cases, patients have been/will be selected, taking comorbidity into account. Multiple advanced neuroscience platforms are being used to evaluate an extensive set of molecular and cellular param
In the second half of this project, a selection of the cellular models will, with our Pharma partners, be up-scaled to provide “industry-standard” cellular assays for compound screening. During the remainder of the project, we will refine diagnostic tools, use novel genomic and cellular features to improve disease classification and discriminate specific patient subtypes. Where possible we will design case studies, with our Pharma partners, in precision medicine: to identify patients with a genetic change whose consequences can be reproducibly ameliorated in vitro by an approved medication. Such case studies will be recommended to the patient and clinician as a double-blinded, N-of-one crossover case study to evaluate the clinical utility of a medication precisely indicated for that person. For a subgroup of patients we create medication that would tremendously improve their quality of life.

COSYN is a crucial next step in “decoding” the genetic findings via intensive focus on the clinical and molecular comorbidities of ID, autism, and schizophrenia.
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