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COSYN:  Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders

Starting date 4 01/01/2016
Duration in months 5 60

Abstract

COSYN integrates outstanding European academic and three large Pharma to exploit genomic findings for intellectual disability (ID), autism, and schizophrenia. We capitalise on comorbidity, from clinic to cells and synapses, and have access to large existing samples. We focus on rare genetic variants of strong effect in patients with clinical comorbidity. Our aims are:
(1) Understand comorbidity by comparing symptom and syndrome overlap with novel neurobiological criteria;
(2) Elucidate mechanisms of comorbidity using neurobiology for the major genomic clue of synaptic dysfunction to unravel the cellular mechanisms of comorbidity;
(3) Generate novel neuronal cell models by using advanced technologies to make neurons from carefully selected patients, and use genome editing to create or correct genetic variants. Multiple advanced neuroscience platforms are in place to evaluate an extensive set of molecular and cellular parameters, and to identify alterations in synaptic biology characteristic of ID, autism, and schizophrenia. These cellular models will, with Pharma partners, be up-scaled to provide “industry-standard” cellular assays for compound screening;
(4) Refine diagnostic tools, use novel genomic and cellular features to improve disease classification and discriminate specific patient subtypes; and
(5) Case studies in precision medicine: with Pharma partners, identify patients with a genetic change whose consequences can be reproducibly ameliorated in vitro by an approved medication.
Recommend to the patient and clinician a double-blinded, N-of-one crossover case study to evaluate the clinical utility of a medication precisely indicated for that person. COSYN is an integrated, state-of-art, bench-to-bedside programme focused on personalised therapeutics. 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.

List of Beneficiaries

1 KAROLINSKA INSTITUTET KI Sweden
2 INSTITUT PASTEUR IP France
3 MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V. MPG Germany
4 UNIVERSITAETSKLINIKUM BONN UKB Germany
5 CARDIFF UNIVERSITY CU United Kingdom
6 HELSINGIN YLIOPISTO UH-FIMM Finland
7 STICHTING VU-VUMC VU/VUmc Netherlands
8 REGION HOVEDSTADEN REGIONH Denmark
9 SYNAPTOLOGICS BV Sylics Netherlands
10 CEGAT GMBH CEGAT GMBH Germany
11 LIFE AND BRAIN GMBH L&B Germany
12 H. LUNDBECK AS H. LUNDBECK A/S Denmark
13 F. HOFFMANN-LA ROCHE AG ROCHE Switzerland
14 PFIZER LIMITED PFIZER United Kingdom
15 VERENIGING SAMENWERKENDE OUDER- EN PATIENTENORGANISATIES


COSYN integrates outstanding European academic and industry groups to exploit the improved knowledge of the comorbid basis and clinical overlap of intellectual disability (ID), autism, and schizophrenia. We will focus on comorbidity at multiple levels, from clinical manifestation to cellular & synaptic function. We capitalize on substantial prior investments in patient diagnosis, sample ascertainment, comprehensive genomic evaluation, stem cell biology, and robust platforms that can manipulate and evaluate neural cells derived from patients. COSYN will further our understanding of disease comorbidity, create novel diagnostic tools and generate new cellular assays enabling compound screening and development of drug treatment strategies. We will merge the concerted efforts of outstanding EU groups, and have attracted the intellectual and material contributions from three large Pharma companies. Most COSYN partners have successfully collaborated on high-impact science for many years and are therefore in an excellent position to achieve the
Objectives The comorbidity amongst the three cardinal psychiatric disorders (ID, autism, and schizophrenia) is the focus of this application. These disorders cause immense disease burden, and are highly comorbid at clinical syndromes and symptoms. COSYN partners have contributed to recent major advances for each disorder, and the findings strongly implicate biological processes at neuronal synapses. In parallel, new technology enables interrogation of human cells from patients at unprecedented depth, precision and multilevel integration. These developments now allow us to probe critical aspects of neuronal dysfunction in cells from patients with ID, autism, and schizophrenia. COSYN aims to implement a multi-modal evaluation of the clinical, molecular and cellular comorbidity of these disorders.

Specifically, COSYN has the following aims:

1) Understand comorbidity. A major impediment to progress in therapeutics for psychiatric disorders like ID, autism, and schizophrenia is incomplete knowledge of the fundamental pathophysiology. The clinical reality is that these groups of patients often have overlapping features, occasionally at the full syndrome level, but more frequently in terms of shared features. Disorders are now defined using overlapping clinical signs and symptoms and not with reference to fundamental biology. COSYN directly aims to improve this by comparing symptom and syndrome overlap with novel neurobiological criteria (Aim 2). This aim will help synthesize novel diagnostic criteria for patients with clinical and molecular comorbidity (Aim 4).

2) Elucidate comorbidity mechanisms using neurobiology. Extraordinary international cooperation is yielding novel insights in the genetic basis of ID, autism, and schizophrenia. Crucially, the genetic results implicate synaptic dysfunction. COSYN therefore aims to apply neurobiological knowledge of synapses to understand synaptic dysfunction common to these disorders. COSYN has unique access to patient cohorts and knowledge of specific variants in genes strongly implicated in at least two of ID, autism, and schizophrenia, which will enable the unraveling of cellular mechanisms of comorbidity. This aim will inform novel diagnostic criteria (Aim 1).

3) Generate novel neuronal cell models. COSYN will use advanced technologies to make neurons from carefully selected patients (Aim 2). COSYN will produce novel cellular models with maximal relevance to individual patients: neurons derived from the patients themselves. Modern genome editing will be exploited to engineer (or correct) informative genetic variants. High-content and high-resolution platforms are in place to evaluate and integrate an extensive set of molecular and cellular parameters, and to identify alterations in synaptic biology characteristic of ID, autism, and schizophrenia. This aim will yield novel validated models that, Associated with our Pharma partners, will be up-scaled to provide new “industry-standard” cellular assays for compound screening.

4) Develop diagnostic tools. Using insights from Aim 1-3, COSYN will define novel genomic and cellular features that can improve disease classification and discriminate specific patient subtypes. This aim will enable precision medicine (Aim 5), and could improve efficacy of clinical trials.

5) Case studies in precision medicine. With our Pharma partners, we will take initial steps towards precision medicine. We will identify patients with a genetic change whose consequences can be reproducibly ameliorated in vitro by an approved medication. Then, we will recommend to the patient and clinician a double-blinded, N-of-one crossover case study to evaluate the clinical utility of a medication precisely indicated for that person. A research assistant will conduct literature reviews to summarize the risks and benefits of the medicines under consideration and discuss with the clinician the scientific structure of a high-quality medication trial (structure, assessments, etc.) and also assist the clinician in identifying the permissions required. This aim will produce proof-of-concept case studies relevant to new disease classification and therapy.

Thus, COSYN is an integrated, state-of-the-art, bench-to-bedside, DNA-to-therapy programme focused on patient-centred therapeutics that capitalizes on prior investments that enabled the genomic revolution. 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.
Uniqueness COSYN is a unique consortium, targeting an exceptionally relevant topic using multiple advanced technologies with outstanding specialists from academia, innovative small/medium enterprises (SME), and exceptional input and full participation from large Pharma companies.

COSYN features:

  • Highly relevant topic: cardinal psychiatric disorders with exceptional but unexplained comorbidity that cover 20% of all societal burden of brain disorders (ID, autism, and schizophrenia);
  • Tightly interconnected, highly focused project with strong central command/control and experts with a history of successful collaboration to ensure rapid progress;
  • A unique project: reaching out to patients across Europe, understanding the comorbidity of their symptoms at multiple levels, from clinical manifestation to synaptic function, generating the best possible models for compound screening (neurons derived from the patients themselves) and reaching back to the patient in proof-of-concept case studies;
  • World-leading experts in clinical psychiatry, psychiatric genomics, stem cell biology, neurobiology, compound screening, and in vivo pharmacology;
  • Highly successful scientists: for instance, 121 authorships on Nature, Science, Cell, and Nature Genetics papers, and 50+ unique papers in Nature, Science, and Cell ;
  • Innovative SME partners that provide advanced technologies, such as the StemCellFactory (robotized iPSC production, Figure 6) and automated in vivo pharmacology;
  • Exceptional participation and commitment of Pharma: three of the world leaders in the business are full and committed COSYN partners (Lundbeck, Roche and Pfizer);
  • Pharma partners provide substantial extra funding, increasing the impact force of EU budget (108 extra person months are committed in addition to the budge requested from the EU);
  • Large impact for patients and society: COSYN is in a unique position to deliver new diagnostics, new cellular assays and validated compounds to improve EU health care; and
  • EU competitiveness: new diagnostics, cellular assays, and validated compounds will strengthen the international position of EU-based SMEs and large Pharma, and create new jobs in the EU.

 

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