Pathobiology of the serpinopathies

Lead Research Organisation: University of Cambridge
Department Name: Haematology

Abstract

We have previously described a new class of disease that we have called the serpinopathies. These occur as a result of mutations in members of a family of proteins called the serine protease inhibitors or serpins. Mutations in these proteins cause them to change size and shape with either aberrant tissue deposition or loss of function. The serpinopathies encompass a wide spectrum of disease that is as diverse as cirrhosis, thrombosis, angioedema, emphysema and more recently dementia. We now propose to define the mechanisms by which mutations in members of the serpin superfamily cause the serpinopathies. In particular, we will use protein, cell and fly models to define how the abnormal proteins form, how they are handled by cells and how they cause cell death. In addition we will develop antibodies to neuroserpin so that we can detect the abnormal protein in animal and human tissues. Finally, we will define how the body clears these abnormal conformations of protein from the circulation and how they can excite white cells to cause inflammation and further tissue damage. Taken together, this programme of work will provide new insights into many different conditions. It is the long-term aim of our laboratory to develop strategies to treat the wide range of diseases that comprise the serpinopathies.

Technical Summary

We have used biochemistry, biophysical analysis, crystallographic studies, cell biology, monoclonal antibodies, fly and mouse models to show that naturally occurring mutations in members of the serine proteinase inhibitor (serpin) superfamily result in abberant conformational transitions to cause disease. The most common of these is the sequential linkage between the reactive centre loop of one molecule and beta-sheet A of another. This process of loop-sheet polymerisation results in the retention of ordered serpin polymers within the cell of synthesis. Polymerisation of mutants of antitrypsin, antithrombin, C1 inhibitor and antichymotrypsin cause cirrhosis, thrombosis, angioedema and emphysema respectively. More recently we have described the same process in a neurone specific serpin, neuroserpin, to cause a novel dementia that we have called Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). We have now described 4 mutants of neuroserpin that cause FENIB and have demonstrated a genotype-phenotype correlation that can be explained by the rate of intracellular polymerisation. In view of their common mechanism we have grouped these diseases of the serpins together as the serpinopathies and have used them as a paradigm for a broader class of disorders that we have called the conformational diseases. The serpinopathies provide a structurally defined model of protein aggregation that causes disease. We propose to use biochemistry, cell biology and fly models to address the following questions in this programme of work: a) What are the pathways that underlie conformational transitions of neuroserpin and can we develop strategies to block polymerisation in vitro and in vivo? b) How are polymers handled by neurones? c) How do polymers cause cell death in a Drosophila model of a serpinopathy? d) Can we develop monoclonal antibodies to detect polymeric neuroserpin in vitro and in vivo? and e) How are polymers cleared from the circulation and how do they mediate their pro-inflammatory effects within the lung? These studies, although focused on neuroserpin and a1-antitrypsin, are applicable to many of the mutations in serpins that underlie the serpinopathies. The long-term aim of our work is to understand mechanisms of disease caused by the serpinopathies (from pathological conformational transitions to pathways of cell toxicity) so that we can develop novel therapeutic strategies to treat the associated clinical syndromes.

Publications

10 25 50
 
Description Chair, Scientific Priorities Committee, 100k Genomes, Department of Health, UK
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact I am Deputy Chair, Scientific Advisory Committee, 100,000 genomes project (2016-). This national programme aims to embed genomics within the NHS
 
Guideline Title NSF for COPD
Description NSF Guidelines on COPD
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
Impact My work has contributed to the supporting scientific evidence to develop guidelines for the identification and management of individuals with COPD. ; The guidelines are currently being considered and have yet to be published.
 
Description Alpha-1 Foundation Grant/Alpha-1 Foundation
Amount £27,170 (GBP)
Organisation Alpha-1 Foundation 
Sector Charity/Non Profit
Country United States
Start 09/2010 
End 08/2011
 
Description Alzheimer's Research UK Studentship
Amount £75,294 (GBP)
Funding ID ART-PhD2006-5 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description Alzheimer's Research UK grant
Amount £152,986 (GBP)
Funding ID ART-PG2008-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 07/2011
 
Description BB/H003843/1 Quantitative approaches to defining normal and aberrant protein homeostasis - co-applicant
Amount £2,467,180 (GBP)
Funding ID BB/H003843/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2010 
End 08/2015
 
Description BLF June Hancock Mesothelioma Research Fund grant
Amount £118,690 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 08/2011
 
Description Diabetes UK PhD Research Studentship
Amount £70,500 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description European Laurells Training Award
Amount £40,700 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 09/2011 
End 10/2011
 
Description GSK Grant to develop monoclonal antibodies to detect fragments of surfactant protein D
Amount £405,163 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 08/2008 
End 07/2011
 
Description GSK Grant to identify small molelcules to treat alpha-1-antitrypsin deficiency
Amount £220,087 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 09/2009 
End 08/2012
 
Description MRC Clinical Research Training Fellowship
Amount £187,415 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2007 
End 07/2010
 
Description MRC Clinical Training Fellowship
Amount £193,232 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description MRC Clinician Scientist Fellowship
Amount £1,024,240 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2007 
End 07/2011
 
Description MRC Programme Grant
Amount £1,797,011 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2011 
End 06/2016
 
Description MRC/EPSRC Life Science Interface Research Grant
Amount £1,900,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2007 
End 07/2012
 
Description NIHR BRC Training and Capacity Building at the University of Cambridge
Amount £1,600,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Cambridge Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 09/2007 
End 08/2012
 
Description WT Studentship
Amount £141,477 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2007 
End 09/2011
 
Description WT/MRC Neurodegenerative Diseases Strategic Award
Amount £3,155,690 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2010 
End 07/2014
 
Description WT/MRC Neurodegenerative Diseases Strategic Award
Amount £3,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2010 
End 08/2014
 
Description Wellcome Trust PhD Training Programme for Clinicians
Amount £6,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2008 
End 08/2013
 
Title Monoclonal antibodies to the pathological conformer of antitrypsin 
Description Monoclonal antibodies to the pathological conformer of antitrypsin 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact This reagent has allowed us to detect pathological polymers in vitro and in vivo and is being used to screen small molecules to block the polymerisation of Z antitrypsin. These will ultimately be used to treat the associated liver and lung disease 
 
Description Small molecules to treat antitrypsin deficiency 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution GSK will undertake a 'black box' screen to look for small molecules to block the polymerisation of mutant antitrypsin. We will help to characterise the hits
Collaborator Contribution GSK will undertake a high throughput screen to look for small molecules to block the polymerisation of mutant antitrypsin. We will help to characterise the hits
Impact GSK will undertake a 'black box' screen to look for small molecules to block the polymerisation of mutant antitrypsin. We will help to characterise the hits
Start Year 2009
 
Description Small molecules to treat antitrypsin deficiency 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution Novartis will undertake a 'black box' screen to look for small molecules to block the polymerisation of mutant antitrypsin
Collaborator Contribution Novartis will undertake a 'black box' screen to look for small molecules to block the polymerisation of mutant antitrypsin
Impact Novartis will undertake a 'black box' screen to look for small molecules to block the polymerisation of mutant antitrypsin
Start Year 2008
 
Title Small molecules to treat alpha-1 antitrypsin deficiency 
Description Small molecules are being developed to stabilise abnormal conformations in alpha-1 antitrypsin in an attempt to develop small molecules to treat this disease. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact This is an ongoing development. 
 
Description Development of the NSF for COPD 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact This grant funded work on antitrypsin deficiency. Insights in this disease were used to inform the Scientific Section of the NSF on COPD.

See 5.7
Year(s) Of Engagement Activity 2007
 
Description Press release Nature paper 2011 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Work featured on the Today programme, Radio 4 Material World, Naked Scientist, BBC website, Guardian website and in newspapers/websites around the world

Huge response from public, especially patients with antitrypsin deficiency
Year(s) Of Engagement Activity 2011