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.

The environMENTAL project will investigate how some of the greatest global environmental challenges, climate change, urbanisation, and psychosocial stress caused by the COVID-19-pandemic affect mental health over the lifespan. It will identify their underlying molecular mechanisms and develop preventions and early interventions. Leveraging cohort data of over 1.5 million European citizens and patients enriched with deep phenotyping data from large scale behavioural neuroimaging cohorts, we will identify brain mechanisms related to environmental adversity underlying symptoms of depression, anxiety, stress and substance abuse. By linking population and patient data via geo-location to spatiotemporal environmental data derived from remote sensing satellites, climate models, regional-socioeconomic data and digital health applications, our interdisciplinary team will develop a neurocognitive model of multimodal environmental signatures related to transdiagnostic symptom groups that are characterised by shared brain mechanisms. We will uncover the molecular basis underlying these mechanisms using multi-modal -omics analyses, brain organoids and virtual brain simulations, thus providing an integrated perspective for each individual across the lifespan and spectrum of functioning. The insight gained will be applied to developing risk biomarkers and stratification markers. We will then screen for pharmacological compounds targeting the molecular mechanisms discovered. We will also reduce symptom development and progression using virtual reality interventions based on the adverse environmental features - developed in close collaboration with stakeholders. Overall, this project will lead to objective biomarkers and evidence-based pharmacologic and VR-based interventions that will significantly prevent and improve outcomes of environmentally-related mental illnesses, and empower EU citizens to manage better their mental health and well-being.

Chronic Neuropathic Pain is frequently associated with peripheral nerve injury or disease. Peripheral injury activates both neuronal and glial components of the peripheral and central cellular circuitry. While it is widely known that the subsequently altered interactions between neurons and glial cells contribute to pain development and to its chronification, the underlying mechanisms are poorly understood. Developing mechanism-based therapies targeting neuron-glial interactions to treat chronic pain will be crucial for improving the quality of life of many patients. Hence the development of novel therapeutic solutions represents a major challenge that demands a multi-disciplinary approach to decipher and understand pathological mechanisms and to translate them into predictive tools for drug development. The NGN-PET consortium addresses this challenge by forming a highly interdisciplinary team that builds upon expertise in areas of academic research on pain mechanisms, industrial knowhow on human stem cell-based tool development, HTS technologies and drug discovery. To achieve its goal we will develop preclinical model systems and assays which recapitulate the human in vivo situation and which can be interrogated for the identification, validation of molecular targets and the development new treatments. A focus of the project will be chemotherapy induced NP and the interplay between nociceptors, microglia and Schwann cells. NGN-PET will carefully characterize rodent in vivo and in vitro models to identify these mechanisms, and will develop rat and human iPSCs based in vitro systems of neuron-glial co-cultures that can be interrogated for targets and used for compound identification and validation. NGN-PET will thus pose the basis for the translation of these model systems into high throughput screening platforms for pharmaceutical research and drug discovery.