Modelling psychosis using DISC1 human induced pluripotent stem cells

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

Schizophrenia and major mental illness are very common conditions whose aetiology is imperfectly understood and for which our treatments are only partially effective. They are known to be highly familial (genetic) and some genetic risk factors, including those affecteing the DISC locus, are sufficient to cause these disorders in a large proportion of individuals who carry them. It is also known that abnormalities of brain structure and function are closely linked to these genetic factors. The cellular mechanisms underlying these abnormalities and clinical disorder are however still unclear, largely becuase the human brain is inaccessable in vivo. However, it has recently become possible to study brain cells in vitro by reprogramming skin fibroblasts to become neurones and other neural cell types.
We propose to study in vitro neural tissue derived from individuals with and without disease-causing translocation at the DISC locus. First, we will reprogramme their fibroblasts to become pluripotent stem cells, neural progenitors and neurons which will then be extensively validated and characterised. We will then examine how disease risk is conferred at a cellular level through a series of comparative studies of neural progenitor proliferation, neuronal morphology and physiology, and later by focussing specifically on the processes affected DISC1/2 and glutamate (NMDA) receptor expression.

Technical Summary

Schizophrenia and major mental illness are devastating conditions with a combined lifetime prevalence of over 10%. Whilst partially effective treatments are available, none are clearly disease modifying. Notwithstanding important insights provided by animal models there is a great and unmet need for further models of mental illness in order to develop more effective therapies. The t(1;11) translocation1, discovered in a large multiply affected Scottish family in very close contact with the Division of Psychiatry, is one of the strongest single genetic risk factors identified for major psychiatric disorders. Combining genetic discoveries with advances in reprogramming and resulting derivation of human induced pluripotent stem cell lines (hIPS) now allows human based disease models and several studies have demonstrated the feasibility of this approach for both neurological and psychiatric disorders.
The current proposal brings together major strengths in clinical psychiatry - specifically our ongoing and long-term study of the t(1;11) family, neurophysiology, molecular genetics, stem cell biology and in vitro disease modelling. We propose to develop a human in vitro model of psychosis by obtaining and then validating induced pluripotent stem cells, neural progenitors and forebrain neurons from individuals with and without the t(1;11) translocation. We will then conduct a number of comparative studies examining the effects of the translocation on neuronal structure and function, dendritic arborisation and spine density, before examining the effects on DISC1/DISC2 and NMDAR expression.

Planned Impact

In addition to the academic beneficiaries of the proposed work, there are wider impacts that will involve patients, health care providers and the pharmaceutical industry.

1. Patients and health care providers
The fundamental objective of this clinically-driven research proposal is to further our understanding of disease biology in psychosis and to develop a platform to develop and test new and more effective drug treatments. The abnormalities discovered in cells from individuals in the current study are likely to lead to an improved understanding of disease biology, since they address the relevent tissue types in vivo and in human subjects for the first time. These insights will lead to more rational therapies targetted to the underlying abnoramlities in these individuals and therefore may lead to persoanlised treatments targetted to an individuals specific undrelying pathophysiology.

2. Pharmaceutical industry
By elucidating the cellular disease phenotype in the current proposal, this will immediately create a system whereby we can attempt to reverse these changes using existing therapies and new chemical entities. These cells may therefore enable a novel platform for drug developmentusing the most relevent tissue type, in vitro. Potentially this may increase the proportion of effective drugs that entre phase III trials and reduce the need for animal based studies.

Publications

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Description CRACK-IT
Amount £998,000 (GBP)
Funding ID BADIPS 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description Confidence in Global Mental Health Research 2017
Amount £188,567 (GBP)
Funding ID MR/R01910X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2018 
End 02/2019
 
Description EU Framework 7
Amount € 420,000 (EUR)
Funding ID IMAGEMEND 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2014 
End 12/2017
 
Description Eva Lester Bequest to the University of Edinburgh
Amount £400,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 11/2016 
End 11/2019
 
Description NIH R01
Amount $1,959,067 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 08/2013 
End 07/2015
 
Description Sackler Endowment
Amount $500,000 (USD)
Organisation Dr Mortimer and Theresa Sackler Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2012 
End 07/2017
 
Description The Sackler Institute of the Universities of Edinburgh and Glasgow
Amount £1,500,000 (GBP)
Organisation Dr Mortimer and Theresa Sackler Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2020
 
Description Wellcome Trust Strategic Award
Amount £4,750,000 (GBP)
Funding ID 104036/Z/14/Z 
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Title DISC1 Induced Pluripotent Stem Cells 
Description We have successfully reprogrammed fibroblasts from the DISC1 family and made confirmed induced pluripotent stem cell lines 
Type Of Material Cell line 
Provided To Others? No  
Impact This has so far demonstrated proof of concept. 
 
Title DISC1 early iPSC neurons 
Description We have derived neuronal cells from two clones of induced pluripotent stem cell lines: one from a patient carrying a translocation between chromosomes 1 and 11, the other from a karyotypicaly normal subject 
Type Of Material Cell line 
Provided To Others? No  
Impact This material will enable one the hypotheses regarding DISC1 fusion transcripts to be addressed 
 
Title DISC1 translocation cell lines 
Description We have banked fibroblasts and induced pluripotent stem cells from individuals carrying a balanced translocation at the DISC locus (Chromosome 1) and Chromosome 11. 
Type Of Material Cell line 
Provided To Others? No  
Impact The cells will be valuable to the research community (and the pharmaceutical industry) in future. They are required for successful completion of the study but will have important uses outside of the planned investigations 
 
Title EBiSC Deposition 
Description We deposited the cell lines from the studying Bipolar Affective Disorder: Induced Pluripotent Stem Cells (BADiPS) study in the international EBiSC consortium repository. This make the cells visible to the international community but, more importantly, it signals a commitment to string them widely for research into mood disorders and related mental illness. 
Type Of Material Cell line 
Year Produced 2016 
Provided To Others? Yes  
Impact Cell lines have been made available to Janssen and Eli Lilly. 
URL http://www.ed.ac.uk/news/2016/stem-cell-scheme-to-boost-bipolar-studies
 
Description Bioinformatic collaboration with MRC HGU 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided RNA and RNA sequence data from DISC1 iPS-derived neuronal cell lines
Collaborator Contribution Our partners have provided bioinformatic analysis of the data from RNAseq analysis.
Impact We have been able to characterise novel transcripts from DISC1-derived cell lines that may explain the cell's abnormal function and the subsequent development of schizophrenia
Start Year 2015
 
Description Collaboration with Lieber Institute and Astra Zeneca 
Organisation The Lieber Institute for Brain Development
Country United States 
Sector Hospitals 
PI Contribution We have provided carefully quality controlled fibroblast and induced pluripotent stems cells from a well-known family who carry a causal mutation for schizophrenia.
Collaborator Contribution Sample sent to LIBD under MTA and are being processed through their pipelines for the derivation of neuronal tissue and their functional genomic and e-physiology pipelines. They are being compared to large numbers of samples from individuals with schizophrenia where there is no-known causal variant, those with penetrant causal variants and individuals highly burdened with common variants of low-penetrance.
Impact This is multi-disciplinary collaboration between genetics, genomics and cell biology labs at Lieber, Edinburgh - including collaborators in drug development at Astra Zeneca.
Start Year 2016
 
Description Comparative RNAseq analysis of mouse model and human DISC1 t(1;11) translocation cell lines 
Organisation Center for Genomics and Transcriptomics (CEGAT)
Country Germany 
Sector Private 
PI Contribution We have contributed RNA and cell lines to the centre for Genomics and Transcriptomics
Collaborator Contribution CEGAT have provided RNA sequencing analysis of the RNA obtained from human t(1;11) neuronal cell lines and from a mouse model of the translocation
Impact We have characterise a rare human variant that is causal for schizophrenia and related psychiatric disorders
Start Year 2015
 
Description Roslin Cells collaboration 
Organisation Roslin Cells Ltd
Country United Kingdom 
Sector Private 
PI Contribution Roslin Cells have contributed expertise to the expansion, banking, viral pathogen testing and reprogramming of human fibroblast cell lines.
Collaborator Contribution They have provided access to materials, expertise and data (including images).
Impact Multiple cell lines have been provided and banked at 3 geographically distinct locations.
Start Year 2012