New strategies for the inhibition of Infection and Inflammation in Cystic Fibrosis Lung Disease
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed 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.
Organisations
- Queen's University Belfast (Lead Research Organisation)
- Charité - University of Medicine Berlin (Collaboration)
- BELFAST HEALTH AND SOCIAL CARE TRUST (Collaboration)
- Medix Biochemica (Collaboration)
- Albumedix Ltd (Collaboration)
- Randox Laboratories (Collaboration)
- Polyphor AG (Collaboration)
- University College Cork (Collaboration)
- GlaxoSmithKline (United Kingdom) (Project Partner)
Publications
Abdelghany SM
(2012)
Gentamicin-loaded nanoparticles show improved antimicrobial effects towards Pseudomonas aeruginosa infection.
in International journal of nanomedicine
Camper N
(2016)
A secretory leukocyte protease inhibitor variant with improved activity against lung infection.
in Mucosal immunology
Cunningham R
(2016)
Solubility study of tobramycin in room temperature ionic liquids: an experimental and computational based study
in RSC Advances
Deacon J
(2015)
Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase).
in Journal of controlled release : official journal of the Controlled Release Society
Hill M
(2019)
Alginate/Chitosan Particle-Based Drug Delivery Systems for Pulmonary Applications.
in Pharmaceutics
Hill M
(2019)
Formulation of Antimicrobial Tobramycin Loaded PLGA Nanoparticles via Complexation with AOT.
in Journal of functional biomaterials
Massey AS
(2016)
Potentiating the Anticancer Properties of Bisphosphonates by Nanocomplexation with the Cationic Amphipathic Peptide, RALA.
in Molecular pharmaceutics
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. One manuscript has been published. In addition, we have extended our research to include nanoparticle-mediated drug delivery to combat the intracellular bacteria, Klebsiella pneumoniae. This has also resulted in a publication and review article. Finally, functionalisation of alginate/chitosan particles with secretory leukocyte protease inhibitor (SLPI) was shown to help inhibit the inflammatory response associated with lung infections (via inhibition of neutrophil elastase activity) and enhance their interaction with cystic fibrosis mucus (assayed via reduction of the depth of particle penetration into the mucus). These findings have also recently been published. |
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 University of Liverpool to scale up these studies to GMP grade nanoparticles that could be taken forward to clinical trials. |
Sectors | Environment Healthcare 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 | 07/2018 |
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 | 06/2015 |
End | 06/2017 |
Description | Department of Education CAST PhD Award |
Amount | £80,000 (GBP) |
Organisation | Government of Northern Ireland |
Sector | Public |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2020 |
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 | Public |
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 | 09/2013 |
End | 09/2016 |
Description | Knowledge Transfer Partnership |
Amount | £212,000 (GBP) |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 03/2013 |
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 | 09/2013 |
End | 09/2014 |
Description | Real World Clinical Outcomes with Novel Modifier Therapy Combinations in Children with CF |
Amount | € 3,050,000 (EUR) |
Organisation | Cystic Fibrosis Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 06/2020 |
End | 06/2024 |
Description | Research Grant |
Amount | $200,000 (USD) |
Funding ID | CFF-WELDON15G0 |
Organisation | Cystic Fibrosis Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 04/2015 |
End | 04/2017 |
Description | Targeting autophagy with a novel parasite-derived peptide |
Amount | £35,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2018 |
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 | Collaboration with Prof Marcus Mall, Charité Universitätsmedizin Berlin |
Organisation | Charité - University of Medicine Berlin |
Country | Germany |
Sector | Academic/University |
PI Contribution | We have carried out assays for Dr Mall which have contributed to publications |
Collaborator Contribution | Dr Mall has provided training in his laboratory in Germany for researchers from my laboratory since 2012. he has also carried out experiments and assays for us in his lab which has contributed to publications and funding opportunities |
Impact | 1. Taggart CC, Weldon S, Mall MA. At the forefront of cystic fibrosis Basic Science research: 16th ECFS Basic Science Conference. J Cyst Fibros. 2020 Feb 13. pii: S1569-1993(20)30047-3. 2. McKelvey MC, Weldon S, McAuley DF, Mall MA, Taggart CC. Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential. Am J Respir Crit Care Med. 2020 Jan 15;201(2):141-147 3. Brown R, Paulsen M, Schmidt S, Schatterny J, Frank A, Hirtz S, Delaney R, Doherty D, Hagner M, Taggart C, Weldon S, Mall MA. Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease. Am J Respir Cell Mol Biol. 2019 Sep 9 4. Small DM, Brown RR, Doherty DF, Abladey A, Zhou-Suckow Z, Delaney RJ, Kerrigan L, Dougan CM, Borensztajn KS, Holsinger L, Booth R, Scott CJ, López-Campos G, Elborn JS, Mall MA, Weldon S, Taggart CC. Targeting of Cathepsin S Reduces Cystic Fibrosis-like Lung Disease. Eur Respir J. 2019 Jan 17. pii: 1801523. 5. Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, Taggart CC, Herth F, Schultz C, Mall MA. Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis. Eur Respir J. 2018 Mar 29;51(3). pii: 1701910 6. Taggart C, Mall MA, Lalmanach G, Cataldo D, Ludwig A, Janciauskiene S, Heath N, Meiners S, Overall CM, Schultz C, Turk B, Borensztajn KS. Protean proteases: at the cutting edge of lung diseases. Eur Respir J. 2017 Feb 8;49(2). pii: 1501200 |
Start Year | 2012 |
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 |
Country | Switzerland |
Sector | Private |
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 | Invited Seminar, Institute of Ageing and Inflammation, University of Birmingham |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | I gave this invited seminar at the University of Birmingham in November 2019 to outline the various aspects of my research programme in the areas of acute and chronic lung inflammation. The target audience was postgraduate students, postdocs and academic staff and clinical academics |
Year(s) Of Engagement Activity | 2019 |
Description | Lab View 360 - Northern Ireland Science Festival |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 70 members of the public (with approximately 50% school-aged children) attended our annual Northern Ireland Science Festival sponsored event in our laboratories in the Wellcome Wolfson institute for Experimental Medicine on the 15th February 2020. The event comprised a laboratory tour of the whole building with the members of the public shown a variety of research themes (including demonstration of lab activities) during a 3 hour period |
Year(s) Of Engagement Activity | 2020 |
URL | https://nisciencefestival.com/event.php?e=186 |
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 |