Keratinocyte growth factor as a novel treatment in an in vivo human endotoxaemic model of lung injury

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Infection & Immunity

Abstract

In many severe illnesses, such as pneumonia or following a road traffic accident, people develop acute lung problems. For reasons that are unclear, their lungs fail and fill with water making breathing difficult and they require support in an intensive care unit. This is termed ?acute lung injury? (ALI). There is no effective treatment for ALI.
The reason the lung fails involves damage to the delicate lining of cells that allow oxygen to pass into the body. This lining is called the alveolar epithelium. A protein called keratinocyte growth factor (KGF) improves lung repair by increasing the number of lining cells and helping them move to damaged parts of the lung. Humans produce KGF, however, patients who have ALI do not have enough and repair is inadequate.
This study will investigate if additional KGF helps lung repair in an established clinical model of ALI.
If effective, results of this study will lead to a clinical trial of this novel therapy in the prevention and treatment of ALI. This project will also provide new information about mechanisms in the development of ALI which could lead to new therapeutic targets.

Technical Summary

Acute lung injury (ALI) is a common devastating clinical syndrome. ALI occurs in response to a variety of insults, such as trauma and severe pneumonia, and mortality is approximately 50%. ALI is associated with neutrophil activation with the release of cytokines and proteases. The resulting inflammatory damage to the alveolar epithelial and capillary endothelial barrier is central to the severity of lung injury causing pulmonary oedema and acute respiratory failure with the need for mechanical ventilation.
Proliferation of alveolar type II epithelial cells is critical to the restoration of alveolar architecture and recovery from ALI. Keratinocyte growth factor (KGF) specifically promotes epithelial proliferation. In addition, KGF promotes epithelial migration, differentiation and re-epithelialisation of wounds. KGF also downregulates pro-inflammatory cytokines and enhances endothelial cell resistance to injury. In animal models of ALI, KGF reduces alveolar capillary permeability, pulmonary oedema and improves mortality. Despite the therapeutic potential no human studies have investigated the effect of exogenous KGF in ALI. Palifermin is recombinant human KGF, and has biological activity analogous to the native protein. Palifermin is safe and is used clinically for treatment of oral mucositis; associated with chemo- and/or radio- therapy. This study will investigate in vivo if palifermin modulates mechanisms important in alveolar epithelial injury and repair in a safe and validated model of lung injury induced by inhalation of low dose lipopolysaccharide (LPS) in healthy volunteers.
Hypothesis: Treatment with palifermin will decrease lung injury induced by LPS inhalation in humans.
The specific aims of this study are to assess the ability of KGF to attenuate lung injury by measuring
1) alveolar and plasma inflammatory response
2) alveolar epithelial and endothelial function
3) alveolar matrix metalloproteinase activity
4) intracellular signalling and transcription factor activation in the alveolar space
This will be a prospective, randomised, double blind, placebo controlled clinical trial.
Subjects will be randomised to palifermin 60microg/kg or placebo intravenously for 3 days prior to LPS inhalation. The dose and duration of pre-treatment was determined on the basis of experimental and clinical data, and is the normal therapeutic dose for treatment of oral mucositis.
These experiments will represent the first study of exogenous KGF in a human model of ALI and will provide new understanding of the mechanisms by which KGF modulates alveolar injury. If effective this study will inform subsequent clinical trials of KGF in ALI.

Publications

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Barr LC (2013) A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. in American journal of respiratory and critical care medicine

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Fitzgerald M (2014) Is there a need for emerging drugs for the acute respiratory distress syndrome? in Expert opinion on emerging drugs

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McAuley DF (2014) Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. in American journal of physiology. Lung cellular and molecular physiology

 
Description Citation in clinical review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
 
Description Clinical Research Fellowship (Cross)
Amount £196,000 (GBP)
Organisation Department of Health Social Services and Public Safety (DHSSPS) 
Sector Public
Country United Kingdom
Start 08/2010 
End 03/2015
 
Description Clinical Research Fellowship (Shyamsundar)
Amount £159,000 (GBP)
Organisation Department of Health Social Services and Public Safety (DHSSPS) 
Sector Public
Country United Kingdom
Start 08/2007 
End 08/2010
 
Description Developmental Pathway Funding
Amount £504,000 (GBP)
Funding ID MR/J014680/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2012 
End 03/2015
 
Description GSK
Amount £150,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Department Respiratory Research GSK
Sector Private
Country United Kingdom
Start 09/2016 
End 08/2018
 
Description MRC Proximity to Discovery
Amount £15,600 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2016 
End 02/2017
 
Description NIHR clinician scientist award (Shyamsundar)
Amount £913,841 (GBP)
Funding ID CVD/5137/15 
Organisation National Institute for Health Research 
Department NIHR Fellowship Programme
Sector Public
Country United Kingdom
Start 05/2015 
End 04/2020
 
Description Project grant (Cathepsin S)
Amount £473,112 (GBP)
Funding ID MR/P022847/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2017 
End 07/2020
 
Description Project grant (MSC)
Amount £462,200 (GBP)
Funding ID MR/L017229/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2014 
End 08/2017
 
Description Study of the Acute Pulmonary Toxicity of Electronic Cigarettes.
Amount $49,874 (USD)
Funding ID R839 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start  
End 08/2019
 
Title LPS model 
Description Provided expertise to establish the LPS model of ALI at the University of Edinburgh and in a clinical research organisation called Celerion 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Successful grant application to Jules Thorn Trust Ongoing collaboration with GSK 
 
Description Collaboration CC at USCF 
Organisation University of California, San Francisco
Department School of Medicine (UCSF)
Country United States 
Sector Academic/University 
PI Contribution Secondary analysis of the HARP-2 trial to define endotypes in ARDS Grant application to investigate e-cigarette smoking in inducing pulmonary inflammation using the human LPS model
Collaborator Contribution Secondary analysis of the HARP-2 trial to define endotypes in ARDS Grant application to investigate e-cigarette smoking in inducing pulmonary inflammation using the human LPS model
Impact Publication Grant application
Start Year 2016
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Department Translational Pharmacology & Discovery Medicine
Country United Kingdom 
Sector Private 
PI Contribution Involved in the design of and undertaking research programme to test novel molecules to test in models of ALI
Collaborator Contribution Access to novel molecules to test in models of ALI
Impact MRC Proximity to Discovery award, £15,600, 2016 Accelerating the discovery and development of new medicines for the treatment of Acute Respiratory Distress Syndrome (ARDS) through knowledge exchange GSK funding to undertake pre-clinical study to to investigate role of Tregs in ARDS CI for a clinical trial in development to test a GSK drug in ARDS and sepsis
Start Year 2009
 
Description Monocyte depletion 
Organisation University of Edinburgh
Department Respiratory Medicine Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided expertise to establish the inhaled LPS model of ALi
Impact Successful grant application to Jules Thorn Trust Paper in press with European Respiratory Journal
Start Year 2009
 
Title ARENA 
Description Aspirin was tested in this model of ALI and is now being tested in a phase 2 trial in patients with ALI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Informed the design of an ongoing phase 2 trial in patients with ALI (STAR). 
URL https://clinicaltrials.gov/show/NCT01659307
 
Title KARE 
Description Prospective randomised double-blind placebo-controlled phase II single centre trial of Keratinocyte growth factor in acute lung injury which is complete. Funded by NI HSC Research and Development Division. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2014
Development Status Closed
Clinical Trial? Yes
Impact Phase 2 trial in patients with ARDS has been completed. No benefit was seen with KGF. As a result a phase 3 trial under consideration was not undertaken. 
URL http://www.isrctn.com/ISRCTN95690673
 
Title KGF in LPS model 
Description Keratinocyte growth factor (KGF) was tested in this model of ALI and is now being tested in a phase 2 trial in patients with ALI. Funded by HSC Research and Development Division 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Informed the design of an ongoing phase 2 trial in patients with ALI. 
URL http://www.isrctn.com/ISRCTN98813895
 
Title Selective TNFR1 antagonism in ARDS 
Description Selective TNFR1 antagonism as tested in the LPS model of ALI and is now being tested in a phase 2 trial in patients at risk of ALI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Informed the design of a planned phase 2 trial in patients at risk of ALI. 
URL https://clinicaltrials.gov/show/NCT01587807