Project: PONS: Patient-Derived Neurons as a Novel Test System for Schizophrenia Drug Development
Goal:_x000D_The overall project aims at the development of a predictive test system for compound profiling based on induced pluripotent stem cells (IPSC) derived from schizophrenic as compared to autistic patients. This will be achieved by:_x000D__x000D_1. Establishment of human patient-derived neurons from IPSCs_x000D__x000D_2. Establishment of a disease signature by comparison of IPSC-derived neurons with established animal models of schizophrenia and Asperger autism (PCP, DISC1 deficiency, maternal immune activation) by high throughput transcriptome sequencing, proteome analysis as well as histological analyses of synapse stabilization_x000D__x000D_3. Application of known and novel drugs for schizophrenia in IPSC models in vitro and in animal disease models in vivo and in depth characterization_x000D_a) by transcriptome sequencing_x000D_b) by proteome analysis_x000D_c) by histological analysis of synapse stabilization_x000D_d) by behavioural analysis _x000D_e) by analysis of specific drug action through comparison of schizophrenia models to autism models_x000D__x000D_The novel test system as project goal aims at the preparation of potential drugs for the introduction into clinical trials._x000D__x000D_Background: _x000D_Schizophrenia is a devastating illness affecting up to 1% of the world population (Nature Rev. Neurosci. (2005) 6:312). Beside the elaboration of positive (delusions, perceptual disturbances, hallucinations etc.) and negative symptoms (asociality, anhedonia, alogia, impaired decision-making, cognitive deficits etc.) patients suffer from increased risk for drug abuse and comorbid depression resulting in suicide in about 5-10% of the cases (J. Clin. Investig. (2009) 119:706). Therefore schizophrenia is linked to substantial emotional burdens for patient families as well as very high economic costs both in terms of medical expenditure and lost productivity. Asperger-Autism is considered a disorder of neural development characterized by impaired social interaction and the development of restricted, repetitive patterns of behaviour, interests and activities. It is accompanied by alterations in synaptic connectivity._x000D__x000D_While specific pharmacotherapies for Asperger-Autism are lacking, present therapeutic approaches in schizophrenia COly focus on the modulation of dopaminergic transmission (Mol. Psych. (2005) 10:79). Further approaches refer to impaired NMDA receptor activity which led to the introduction of phencyclidine (PCP) models. However, available therapeutic interventions ameliorate positive symptoms to a certain degree but fail with negative, most probably due to the mostly unknown etiology of schizophrenia. New trends in the field aim at the level of signal transduction emerges (Mol. Psych. (2005) 10:79) and the integration of aberrant neurodevelopment. Such novel therapeutic approaches require completely different experimental models and drug screening processes which are not available so far. To meet these demands we plan a novel drug screening platform:_x000D__x000D_Technical and market application:_x000D_This platform will be offered to pharmaceutical companies for target research and preclinical development. The in vitro screening platforms will help to provide significant informations on the functionality of candidate targets and the impact of novel drugs in modelled disease states. Since the central technology of the platform is based on patient-derived neurons, the application also serves for patient stratification in clinical studies._x000D__x000D_Consortium:_x000D_The project integrates the activities of three SMEs, a research institute and a clinical P. CeGaT GmbH, Tübingen is a startup in the field of high throughput sequencing. SYLICs uses mass spectrometry for proteome analysis. Pharmaseed Ltd, Ness Ziona is an established contract research organization with vast and longterm experience in behavioural analysis of animal models for CNS diseases. NMI is experienced in the characterization of synaptic connectivity at a histological level and harbours large cell culture facilities. In collaboration with the Hertie institute of brain research, Tübingen, induced pluripotent stem cell (IPSC) differentiation into neurons has been established. Human patient-derived fibroblasts will be provided by the clinical P Department of Psychiatry and Psychotherapy (DPP), University of Tuebingen, headed by Prof. Fallgatter, treating about n = 750 patients with schizophrenia spectrum disorders per year in its specialiced in- and outpatients facilities.
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Acronym
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PONS
(Reference Number: 7675)
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Duration
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01/06/2013 - 31/05/2016
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Project Topic
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Induced pluripotent stem cells from fibroblasts of schizophrenic and autistic patients will be differentiated in neurons. This novel in vitro system will be analyzed upon compound action at transcriptome, proteome and histological level and matched with cultured rodent derived neurons.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 9
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Project partner
