Pathobiology of alpha-1-antitrypsin deficency and the serpinopathies

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

The serine proteinase inhibitors or serpins are a family of proteins that play an important role in controlling enzymes within the human body. Naturally occurring mutations cause the protein to change shape and accumulate as chains of polymers within the cell of synthesis. This causes cell death and hence either cirrhosis (if the protein accumulates within the liver) or dementia (if it accumulates within the brain). We propose to assess the mechanism by which polymers form and their effect on the cells in which they are synthesised. We also propose to determine the mechanism of action of small molecules that we have identified that can block polymer formation in the test tube and reduce the accumulation of mutant protein in a cell model of disease. We have shown that mutations that favour the formation of polymers also favour the formation of an inactive latent conformation. We propose to develop new monoclonal antibodies to the latent conformation of the serpins alpha-1-antitrypsin and neuroserpin so that we can identify them in biological tissues and so evaluate their role in disease. Polymers of alpha-1-antitrypsin form spontaneously within the lungs of individuals with alpha-1-antitrypsin deficiency where they inactivate alpha-1-antitrypsin as a proteinase inhibitor as well as acting as a chemoattractant to recruit inflammatory cells to the lung. We will use our antibody to polymers of alpha-1-antitrypsin to develop a new assay to image pathological polymers within the lung. This will provide useful information on the clearance of polymers from the lung and perhaps the progression of lung disease in individuals with alpha-1-antitrypsin deficiency.

Technical Summary

We have used a wide range of techniques 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. Perhaps most striking is our description of 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). A central feature of these conditions is 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 in association with disease. We propose to use the small molecules, crystal structures, cell lines, monoclonal antibodies, fly models and the genetic screen that were generated in the last programme grant to address the following specific questions: (i) what are the conformational transitions underlying the serpinopathies? (ii) what is the effect of small molecules that block the polymerisation of alpha-1-antitrypsin? (iii) what is the cellular response to the retention of ordered serpin polymers within the endoplasmic reticulum? (iv) can we prepare monoclonal antibodies to latent alpha-1-antitrypsin and neuroserpin in order to define their role in disease? (v) what is the role of polymers in lung disease in alpha-1-antitrypsin deficiency? These studies, although focused on alpha-1-antitrypsin and neuroserpin, 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

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Bafadhel M (2011) Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. in American journal of respiratory and critical care medicine

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Belorgey D (2011) Characterisation of serpin polymers in vitro and in vivo. in Methods (San Diego, Calif.)

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Briggs AH (2017) Development of the Galaxy Chronic Obstructive Pulmonary Disease (COPD) Model Using Data from ECLIPSE: Internal Validation of a Linked-Equations Cohort Model. in Medical decision making : an international journal of the Society for Medical Decision Making

 
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
 
Description Alpha-1 Foundation Pilot & Feasibility Study
Amount £27,170 (GBP)
Organisation Alpha-1 Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2010 
End 08/2011
 
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 10/2008 
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Description Amgen Foundation Summer Scholarship 2011 (through University of Cambridge)
Amount £2,000 (GBP)
Organisation Amgen Inc 
Sector Private
Country United States
Start 06/2011 
End 08/2011
 
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 10/2010 
End 09/2015
 
Description BLF Asbestos-Related Disease PhD Studentship
Amount £93,156 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description BLF June Hancock Mesothelioma Reserch Fund Grant
Amount £118,690 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 08/2012
 
Description CLDF William Holloway Alpha-1 ATD Research Fellowship (PhD Studentship)
Amount £75,000 (GBP)
Organisation Children's Liver Disease Foundation (CLDF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2014
 
Description Diabetes UK PhD Research Studentship
Amount £70,500 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
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Description EPSRC/GSK CASE Industrial PhD Studentship
Amount £50,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2015
 
Description EPSRC/GSK CASE Industrial PhD Studentship
Amount £51,121 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2011 
End 09/2015
 
Description European Laurell's Training Award
Amount £43,859 (GBP)
Organisation Grifols 
Sector Private
Country Global
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Description GSK Discovery Partnerships with Academia
Amount £250,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Department Discovery Partnerships with Academia
Sector Private
Country Global
Start 08/2012 
End 08/2015
 
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 10/2008 
End 09/2011
 
Description GSK grant to identify small molecules to treat alpha-1-antitrypsin deficiency
Amount £220,087 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2009 
End 09/2012
 
Description INSPIRE Award from Academy of Medical Sciences/Wellcome Trust
Amount £5,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2014
 
Description MRC Clinical Training Fellowship
Amount £193,232 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2011 
End 07/2014
 
Description MRC Senior Clinical Fellowship
Amount £1,638,935 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2012 
End 07/2017
 
Description MRC programme grant
Amount £2,047,855 (GBP)
Funding ID MR/N024842/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2021
 
Description MRC/EPSRC Life Science Interface Research Grant
Amount £1,900,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 09/2012
 
Description NIHR BRC Training & Capacity Builing ast the University of Cambridge
Amount £1,600,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Cambridge Biomedical Research Centre
Sector Public
Country United Kingdom
Start 08/2007 
End 07/2012
 
Description Rose tress Trust project grant
Amount £48,546 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description WT PhD Training Programme for Clinicians
Amount £6,000,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 07/2013
 
Description WT Strategic Award for CIMR
Amount £4,200,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2012 
End 11/2017
 
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 grant to the Cambrdge University Research Society
Amount £564,500 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2010 
End 07/2011
 
Description WT/MRC Neurodegenerative Diseases Strategic Award
Amount £3,155,690 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description WT/MRC Neurodegenerative Diseases Strategic Award
Amount £3,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2014
 
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 GSK small molecules to blcok polymeristaion of antitrypsin 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Provided monoclonal antibody, ELISA assay and expertise on the biology of antitrypsin deficiency
Collaborator Contribution Providing small moelcules as tools to block polymerisation in cell modelsof disease
Impact On oging
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 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
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