New strategies for the inhibition of Infection and Inflammation in Cystic Fibrosis Lung Disease

Lead Research Organisation: Queen's University of Belfast
Department Name: Medicine Dentistry and Biomedical Sci

Abstract

Cystic Fibrosis (CF) is one of the most common genetically inherited illnesses in the UK and worldwide. Although a number of organs are involved in the disease progress the vast majority of individuals with the disease will die as a result of respiratory failure due to a combination of overwhelming infection and lung tissue destruction as a result of excessive inflammation. Currently, antibiotics are used to treat the infection in the CF lung and tobramycin (tobi) has been developed and used to successfully reduce infection and improve lung function. However, despite the reduction in infection, the number of bacteria still resident in the CF lung remains very high due to the inability of tobi to penetrate into the thick secretions (mucus and sputum) present in the CF lung. Also, tobi only remains in the lung for a short period of time before it is removed from the body. Another drug, called SLPI, has previously been used in clinical trials to treat CF lung disease. SLPI works to reduce the inflammation in the CF lung which can be damaging to lung tissue. We propose linking tobi to SLPI in order to develop a dual-based drug that will be able to combat inflammation and infection more effectively in the CF lung. The SLPI part of this drug will bring tobi to the sputum/mucus-rich areas of the CF lung where it will be cleaved off and act directly on bacteria that it would not normally be able to kill. In addition, we have recently shown that SLPI itself can be damaged by inflammation in the lung thus reducing its effectiveness. We propose making a more stable variety of SLPI that will not be damaged in the CF lung and therefore be more effective in decreasing CF lung inflammation. We will link tobi to this new SLPI variant to make a dual-based drug. For its part, the new SLPI variant will inhibit inflammation more effectively than native SLPI. Therefore, this combined SLPI-tobi drug should be more effective at reducing inflammation and infection in the CF lung and thus stabilise lung function in treated patients. Ultimately, we hope that the SLPI-tobi drug will be a mainstay therapy for the treatment of CF lung disease and prolong the lives of patients receiving it. We also envisage that SLPI-tobi will find use in other chronic lung diseases such as Chronic Obstructive Pulmonary Disease which is also characterised by excessive inflammation and infection.

Planned Impact

Who Will Benefit from this Research? Specifically, the research and drug leads proposed will benefit CF sufferers, improving their quality and length of life. Towards this over-arching goal, others will benefit. For example, most pharmaceutical companies have an active interest in development of new treatments for inflammatory lung disorders such as CF, and are therefore likely to be interested in the research outlined in our proposal. Chiron, who originally developed tobi, and who are now part of Novartis, may be interested in a new product combining the features of tobi with an anti-inflammatory (SLPI). Likewise, Amgen who bought over Synergen (the company responsible for recombinant SLPI production) may also be interested in a protease-resistant variant of SLPI. Other pharmaceutical companies with an interest in respiratory disease including GSK and AZ may also be interested in these potential therapeutics. Clearly, charities linked to CF including the British CF Trust and the Cystic Fibrosis Foundation will also be interested in the development and use of mutant SLPI and SLPI-tobi as well. Such charities generally have excellent links with local and national governments who would also be interested in the development of new therapies, especially therapeutics that could reduce healthcare costs and improve quality of life as well as being of use in the treatment of other chronic lung diseases with an inflammation/infection component most significantly COPD. How will they benefit from this research? The synthesis of a combined anti-inflammatory/antibiotic (SLPI-tobi) would be a significant step forward in the development of a new generation of drugs for the treatment of chronic lung diseases such as CF and may herald the development (by pharma or academia) of other combined anti-inflammatories/antibiotics using the novel chemical approaches we have employed in this proposal. It would be envisaged that the production and development of mutant SLPI and SLPI-tobi could be reasonably rapid (~5 years) as the safety and efficacy of both SLPI and tobi as aerosolised therapies has already been established. The applicants and PDRAs/PhD student employed on this proposal will also gain unique expertise in the development of recombinant proteins and protein-antibiotic hybrids for therapeutic use which they could use for future employment in industry or for the development of future novel research ideas. What will be done to ensure that they benefit from this research? A major part of the proposal will be the engagement with the GSK CEDD and we would plan to ensure good communications between the applicants in Queen's and the CEDD. Apart from the in-built time spent by some of the team members at the CEDD (for linker studies and bulk recombinant synthesis) we would plan emailed and tele-conference communications on a weekly or bi-weekly basis for updates and troubleshooting as well as planned formal site visits every 3 months. The primary goal is to develop two products - NE-resistant SLPI and tobi linked to NE-resistant SLPI - for the purposes of development into drugs for initial treatment of CF and then for other lung diseases. This would be done in collaboration with GSK and the Knowledge Enterprise Unit at Queen's. Given the combined experience of the applicants in organic synthesis, recombinant technology and clinical evaluation of drugs we would envisage that the project would be successful and deliver the two products above.
 
Description The main aim of this project is to design more effective drug strategies for the treatment of chronic lung diseases such as Cystic Fibrosis (CF). The current problem in the treatment of CF lung disease is the poor bioavailability of drugs to the CF lung due to barriers such as mucus and DNA. Therefore, we wish to develop new ways to get around the problem of poor penetration of drugs to the CF lung. We are implementing two ways to get around this - 1. the design and development of nanoparticles for the effective delivery of antibiotics and anti-inflammatories to the CF lung and 2. design and delivery of novel prodrug formulation combining antibiotics and anti-inflammatories via a activable chemical linker that is activated in vivo in the CF lung. The main project findings from Objective 1 have been the development of novel nanoparticle-based strategies for the delivery of antibiotics to the CF lung. These nanoparticle formulations offer a significant improvement upon the 'naked' delivery of antibiotics as they penetrate CF sputum plugs more effectively that the naked drug and kill bacteria in the sputum plug more efficiently. We have drafted two manuscripts which are currently under review. For objective 2, experiments that are ongoing including the synthesis of prodrug entities that combine antibiotics to anti-inflammatory molecules via a chemical linker that will become activated in vivo in the CF lung. We are also making site-specific modified anti-inflammatory proteins that will be more effective (more resistant to proteolysis) in the CF lung and that also be chemically linked to antibiotics
Exploitation Route We think both objectives outlined above - the design of novel nanoparticle-based strategies and novel prodrug entities for the treatment of CF lung disease - could both be commercially exploited. We are currently in discussions with the GSK CEDD in Stevenage regarding our nanoparticles-based findings to see if we can further investigate their potential in models of lung disease used by the CEDD. We would hope that positive findings from these in vivo findings may lead to further development of the nanoparticle strategies for first-in-man studies
Sectors Environment,Pharmaceuticals and Medical Biotechnology

 
Description The spin out company referred to in the previous report as Actus Pharma was actually incorrect. The spin out company that was briefly formed by Prof Chris Scott (a co-applicant on the above grant) is no longer operational. However, Prof Scott has licensed out one of his nanoparticle formulations to Palleon Pharma in the USA.
First Year Of Impact 2017
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description Cathepsin S targeting as a therapy for CF lung disease
Amount £143,586 (GBP)
Funding ID WELDON18G0 
Organisation Cystic Fibrosis Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2020
 
Description Cystic Fibrosis Foundation Research Grant
Amount £148,123 (GBP)
Funding ID WELDON15G0 
Organisation Cystic Fibrosis Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2015 
End 06/2017
 
Description EPSRC Cross-Disciplinary Grant - Enabling phosphorous and peptide chemical biology using ionic liquids
Amount £201,658 (GBP)
Funding ID EP/I016104/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 01/2010 
End 01/2011
 
Description EU Health PRogramme
Amount £800,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2016
 
Description Knowledge Transfer Partnership
Amount £212,000 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 04/2013 
End 03/2016
 
Description Proof of Concept
Amount £106,000 (GBP)
Funding ID PoC 409 
Organisation Invest Northern Ireland 
Sector Public
Country United Kingdom
Start 10/2013 
End 09/2014
 
Description Targeting autophagy with a novel parasite-derived peptide
Amount £35,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 08/2019
 
Title Cleaved SLPI antibody 
Description Generation of a new antibody which is being developed in partnership with a diagnostics company (Randox) for use in a near patient bacterial test 
Type Of Material Antibody 
Provided To Others? No  
Impact 1 patent application filed to UK Intellectual property office (1414079.2) 
 
Title Protease Resistant Inhibitors 
Description Recombinant variants of established protease inhibitors that were modified to make them more resistant to proteolysis 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact 1 paper published in Molecular Therapy and one pending submission 
URL http://www.ncbi.nlm.nih.gov/pubmed/25189740
 
Title Development of a novel transgenic model to evaluate the role of cathepsin S in chronic lung inflammation 
Description This model was derived form the Scnn-Tg (betaENaC-Tg) mouse model which is a model of chronic lung inflammation and is characterised by elevated lung inflammation, lung damage, mucus obstruction and a bacterial clearance defect (Mall M et al, Nat Med. 2004 May;10(5):487-93.). We have shown elevated cathepsin S (CTSS) levels in the lungs of the Scnn-Tg mouse and to establish a role for CTSS in chronic lung disease, we genetically crossed the Scnn-Tg model onto a CTSS deficient background. The newly generated line (Scnn-Tg/CTSS KO) mice exhibited decreased lung inflammation, lung damage and mucus obstruction compared to the parental Scnn-Tg line and this finding was published in the European Respiratory Journal (Eur Respir J. 2019 Jan 17. pii: 1801523). 
Type Of Material Data analysis technique 
Year Produced 2019 
Provided To Others? Yes  
Impact Too early to describe but the findings have been published in local media outlets in Northern Ireland (https://www.belfasttelegraph.co.uk/news/northern-ireland/qub-breakthrough-offers-hope-to-lung-disease-patients-37887100.html). 
URL https://erj.ersjournals.com/
 
Description CF MATTERS 
Organisation University College Cork
Country Ireland 
Sector Academic/University 
PI Contribution Work Package leader on Host Defense research study
Collaborator Contribution Our partners will run a clinical trial in CF patients and we will evaluate the host defense response in sputum samples obtained from these patients
Impact 0
Start Year 2013
 
Description Consultancy with Albumedix (Nottingham, UK) 
Organisation Albumedix Ltd
Country United Kingdom 
Sector Private 
PI Contribution I have provided expert advice via consultancy to the Albumedix team
Collaborator Contribution Albumedix are developing a variant of alpha 1 antitrypsin for the treatment of Cystic Fibrosis lung disease and I have provided them with advice regarding the pre-clinical evaluation of their Alpha 1 antitrypsin molecule
Impact Nothing so far
Start Year 2017
 
Description KTP Randox 
Organisation Randox Laboratories
Country Global 
Sector Private 
PI Contribution We have generated an antibody to a novel biomarker in the lung which is now being developed by Randox into an imunoassay
Collaborator Contribution Randox will develop the antibody on several of their testing matrices to sell initially as a Research Only ELISA followed by development into a near patient assay. As of March 2017 the Research Use Only ELISA had not been released by Randox due to unforeseen technical issues.
Impact A patent application has been filed to the UK Intellectual Property Office (1414079.2)
Start Year 2013
 
Description Knowledge Transfer Scheme 
Organisation Belfast Health and Social Care Trust
Country United Kingdom 
Sector Public 
PI Contribution Transfer of knowledge from university laboratory to hospital laboratory. Dr Nicolas Camper spent time working in Prof Moore's laboratory in the Belfast City Hospital. The objective was to evaluate the effect of nanoparticle-delivered drugs to planktonic and biofilm bacteria compared to 'naked' delivery of these drugs.
Start Year 2012
 
Description Medix Biochemica 
Organisation Medix Biochemica
Country Finland 
Sector Private 
PI Contribution We have developed monoclonal antibodies to the human lung serine protease inhibitor, elafin. These antibodies are now being evaluated for diagnostic development by Medix Biochemica (Espoo, Finland) as a diagnostic for pre-term birth delivery and were developed as part of a Proof of Concept grant funded by InvestNI (PoC 409). The collaboration is at an early stage of development and we hope to move towards a licencing agreement with Medix Biochemica in the near future
Collaborator Contribution Medix Biochemica are currently evaluating the value of the elafin antibodies as a pre-term birth diagnostic. This research is ongoing
Impact None as yet
Start Year 2016
 
Description Polyphor collaboration 
Organisation Polyphor AG
PI Contribution We have established a collaboration with Polyphor, a Swiss biotech company. We have begun evaluating an anti-elastase inhibitor for them in our assays
Collaborator Contribution They have provided us with their anti-elastase inhibitor, POL6014. We have visited with Polyphor and have commenced drafting of an Horizon 2020 grant application with them. The H2020 application successfully progressed to Phase 2 of the application process (January 2017). However, in late February 2017, Polyphor decided to withdraw the application from the phase 2 process due to a change in the company focus.
Impact None
Start Year 2015
 
Title Development of antibodies for cleaved secretory leukocyte protease inhibitor 
Description Development of two monoclonal antibodies that specifically detect a cleaved form of secretory leukocyte protease inhibitor 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2014
Licensed Yes
Impact We are moving towards the production of a Research use Only ELISA for cleaved SLPI. Release of the ELISA has been delayed due to unforeseen circumstances
 
Title Bacterial Detection Test 
Description An antibody has been generated which is being developed wit Randox into a bacterial detection test 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact Still at early stage of development - patent filed (1414079.2) 
 
Description Annual contribution to the Northern Ireland Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The festival presented a range of workshops, talks and interactive activities for young people, parents and schools
Year(s) Of Engagement Activity 2016,2017,2018,2019
URL http://www.nisciencefestival.com
 
Description Cystic Fibrosis Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Appointed to this position in June 2011 . Awarding Body - European Cystic Fibrosis Society, Name of Scheme - Panel member of Scientific Committee

Further engagement with other scientists
Year(s) Of Engagement Activity 2011
 
Description Cystic Fibrosis Open Evening 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 50 parents and patients with CF attended an open evening at our institution to learn about the research we do in the area of CF

Request for follow-up progress from parents and patients
Year(s) Of Engagement Activity 2013
 
Description Research Showcase 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact My EPSRC-related research has been showcased on the Queen's University Belfast website under the 'Impact of Research' weblink on the front page of the Queen's website and under the 'Our Pioneers' section

Further engagement with other scientists
Year(s) Of Engagement Activity 2011
URL http://www.qub.ac.uk/home/Research/ResearchImpact/CaseStudies/SchoolofMedicineDentistryandBiomedical...
 
Description Respiratory Conference 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Elected to this position in February 2011 . Awarding Body - European Respiratory Society, Name of Scheme - Society Elections
Symposia and poster sessions which attracted between 100-800 delegates per session

Increase in scientific profile
Year(s) Of Engagement Activity 2011
 
Description UK Cystic Fibrosis Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact The meeting was designed to present up to date advances to patients and care groups associated with the treatment and care of patients with cystic fibrosis
Year(s) Of Engagement Activity 2015
URL https://www.youtube.com/watch?v=QVz8mCR6rtU