The Cystic Fibrosis Trust is committed to supporting research, which will have an important and/or immediate clinical benefit for those with Cystic Fibrosis and we funded £775,000 of non-gene therapy projects in the last financial year into various aspects of CF such as inflammation, infections and different approaches to treating the underlying cause of Cystic Fibrosis.

In 2008/9, the Lottery-funded work of the UK CF Microbiology Consortium drew to a close. This project investigated various aspects of the CF infections Pseudomonas and Burkholderia cepacia such as transmissibility and virulence. It has led to new ways of detecting infection and opened new areas of research into treating these dangerous pathogens. Four of the young researchers involved have also continued to work in CF research.

Along with this work on infection, the Trust also funded Professor Elborn in Belfast who is investigating the link between infection and exacerbations in the lungs. This complemented the work by Dr Kenna in Edinburgh who was researching the genetics of highly virulent strains of Pseudomonas, and we continued to provide financial support to the Microbiology Lab in Edinburgh, where many CF Centres send their samples for testing.

The CF Trust also worked with the Medical Research Council to create a joint training fellowship in Newcastle using the lungs of those with CF who have had a transplant to determine new treatments for the cycle of inflammation and lung damage in Cystic Fibrosis.

As this cycle is such a problem, the Trust also funded two further projects into inflammation. Dr Schock in Belfast is investigating a protein that controls the body's inflammatory response to infection and which is only produced in low amounts in people with Cystic Fibrosis. In Dundee, Dr Mehta is researching a different protein that his team have discovered links CFTR (the protein that controls the movement of sodium and chloride through the cell lining and which in CF either doesn't, or only partially works) and inflammation.

The fault in CFTR is the underlying cause of the problems in CF and Professor Cuthbert in Cambridge is researching the use of an existing drug to open other channels in the cell walls to allow the movement of sodium and chloride.

Dr Sheppard in Bristol continued his work into potentiators, which are drugs that bind to the CFTR and help it to do its job properly. Many possible potentiators have been discovered and this project will assess them for their effect on CFTR function for specific mutations of the CF gene.

Finally, we funded Dr Fisher in Newcastle who is using a modified bypass machine to increase the number of lungs that are suitable to be transplanted (currently around 75% of available donor lungs are unusable) and a natural anti-inflammatory protein to protect the lungs following transplant.

For full information on CF Trust funded projects, download our Research Grants document or Research Grants by Region document.

Further details of our current research projects can be found on this page. The research can be broken down into four areas: clinical, microbiology, basic science: pharmacology, and basic science: inflammation.

Clinical Research

The Role of Ex-Vivo Lung Resuscitation and Anti-inflammatory Secretory Leucoprotease Inhibitor (SLPI) Therapy in Transforming Unusable Donor Lungs for Effective Use in Human Lung Transplantation.
Grant Holder: Dr A Fisher (PJ 543)
Term/Award: 01.07.08 - 30.06.11 (36 months Project Grant) £ 464,122
Institute: Newcastle University

Lung transplantation produces both an improved quality of life and better survival in advanced cystic fibrosis (CF), with 50% of CF recipients now living >10 years in experienced centres. Unfortunately 30-40% of CF patients accepted for transplant die before a suitable donor lung becomes available. Although a shortage of total donors contributes, the main problem is that 75% of available donor lungs in the UK are considered unusable due to poor function. Our study will tackle this problem by assessing ways to transform unusable donor lungs into lungs suitable for use in clinical lung transplantation.
Unusable donor lungs will be placed on a modified bypass machine called an ex-vivo lung perfusion circuit. We will determine if this improves the function of the unusable donor lung and also assess its effects on lung inflammation, which our previous work shows predicts how well donor lungs work after transplant. At the same time we will assess in a rodent lung transplant model whether treatment with SLPI, a natural anti-inflammatory protein, protects inflamed donor lungs from poor function after transplant. If SLPI proves successful in this model we will translate it to human donor lungs as our express aim is not only to increase the number donor lungs used but to ensure they produce excellent results.

UK Prevalence and impact of depression and anxiety in people with CF and their caregivers.
Grant Holder: Dr A Duff (PJ544)
Term/Award: 19.10.09 - 18.10.12 (36 months Project Grant) £ 20,895
Institute: Leeds Teaching Hospitals NHS Trust

Estimating the prevalence of depression in cystic fibrosis (CF) populations has become important as new evidence indicates that these symptoms may have a significant impact on health outcomes, including adherence to medical treatments, utilisation of health care services, and rates of morbidity and mortality (Reikert, 2005). Results from meta-analysis indicates that depressed patients (sampled from a variety of illness populations), were three times more likely to be non-compliant with medical treatment recommendations than non-depressed patients with a chronic illness (DiMatteo et al., 2000).
This project is groundbreaking in its' multi-centered co-ordination, being part of the international study. Funding is already in place in USA, Germany, Italy, the study being supported by respective national CF Foundations. Applications for funding are underway in Ireland, France and Australia.
Understanding depression and anxiety in this population will determine whether or not routine screening would contribute to improving health outcomes for people with CF, given the recent NICE guidelines of the effective treatment of depression and anxiety via psychotherapy (cognitive behaviour therapy), and pharmacology.

Early detection of lung disease in infants with CF diagnosed by newborn screening using objective, standardised measures of infection, inflammation, lung structure and function.
Grant Holder: Prof. Janet Stocks (PJ550)
Term/Award: 05.01.10 - 04.01.13 (36 months Project Grant) £ 150,000
Institute: University College London

Newborn screening (NBS) for Cystic Fibrosis (CF) was recently introduced throughout the UK but can only be justified if it leads to better treatment. We have shown that lung function may already be impaired in CF babies when they are diagnosed clinically, even when they have no respiratory symptoms. There is, however, limited information about infants diagnosed by NBS, or how best to protect the lungs of these infants. Exciting new treatments such as gene therapy may become available in the next decade and infants with CF diagnosed by NBS have the most to gain from such treatments. However, we need better ways of assessing effectiveness and safety of such treatments before they can be used in this age group.

We will measure lung function, structure and inflammation in CF infants diagnosed by NBS to investigate:
1. Whether such infants have:
a) abnormal lung function by 3 and / or 12 months of age
b) abnormal lung structure by 1 year of age
2. How many have signs of lung infection and inflammation by one year
3. Whether these tests will provide reliable tools for future multicentre clinical trials
4. The feasibility of recruiting NBS infants into this sort of study

Microbiology

Proteomic investigation of the role of bacterial infections in initiating pulmonary exacerbations in CF patients.
Grant Holder: Prof. Stuart J Elborn (PJ545)
Term/Award: 20.01.09 - 19.01.11 (24 months Project Grant) £ 109,397
Institute: The Belfast City Hospital

People with Cystic Fibrosis (CF) are unusually susceptible to lung infections which contribute significantly to a poor prognosis. The majority of lung damage results from the abnormal, destructive action of the patient's immune system during times of extreme inflammation know as pulmonary exacerbations. Exacerbations occur periodically, but their cause remains poorly understood. This proposal investigates if bacteria within the CF lung play a significant role in initiating pulmonary exacerbations. Our key goals are to improve the current understanding of how the bacterial population affects exacerbations. The study will focus on patients chronically infected with Pseudomonas aeruginosa, as this is one of the most common and destructive infecting organisms. In-depth comparisons will be made between all types of bacteria found in sputum samples collected in times of relative good health versus episodes of pulmonary exacerbation. The factors under consideration as potentially contributing to the on-set of symptoms include: (i) the total number of bacteria, (ii) the numbers of individual bacterial species, (iii) the types and levels of secreted bacterial chemicals, and (iv) the chemical composition of the bacterial cells themselves.

The impact of diabetes on the microbiology of cystic fibrosis lung disease
Grantholder: Dr Alan Brown (RS29)
Term/Award: 01.08.10 - 31.07.13 (36 months PhD Studentship) £ 18,000
Institute: University of Exeter

Patients with cystic fibrosis (CF) suffer from serious lung infections caused by a group of bacteria called the Burkholderia cepacia complex (Bcc). These infections cause reductions in lung function and life expectancy. In addition, as CF patients get older they frequently develop diabetes, a condition in which the body cannot control the amount of sugar within the blood due to reduced levels of the hormone, insulin. When CF patients develop diabetes, their lungs become even less efficient, and their life expectancy is further reduced. Various pieces of evidence suggest that the conditions which arise during diabetes (either as a result of the diabetes itself, or its subsequent treatment) might dramatically alter the way that Bcc behaves within the CF lung, and that this may influence the severity of the infection. The proposed research will investigate how bacteria of the Bcc respond to different conditions that are relevant to diabetes (e.g. heightened sugar concentrations and insulin), and then look for evidence of the same responses within clinical samples from CF patients with diabetes. This research will reveal the direct impact that diabetes has on the Burkholderia infections of the CF lung, and help guide the most effective management of CF-related diabetes.

Basic Science : Pharmacology

Use of REFER analysis to optimize the efficacy of CFTR potentiators
Grant Holder: Dr David N Sheppard (PJ547)
Term/Award: 01.09.08 - 31.12.10 (28 months Project Grant) £ 149,773
Institute: University of Bristol

There is currently no cure for the common life-threatening inherited disease cystic fibrosis (CF) that damages or destroys a protein called CFTR causing important organs (e.g. the lungs) to not work properly. With understanding of how CFTR works and how it goes wrong in CF, new therapies for CF patients are being developed. A key approach is to rescue the activity of damaged CFTR proteins (termed CF mutants) with drugs called CFTR potentiators. An ideal CFTR potentiator would bind tightly to CF mutants and restore to them normal levels of CFTR activity. Many chemicals have been identified that act as CFTR potentiators. However, it is unknown how the chemical structure of a CFTR potentiator determines its efficacy (a measure of a drug's ability to elicit a biological response). We propose to address this critical issue for CF drug development. Using a novel analytical method, we will investigate the efficacy with which different CFTR potentiators enhance the activity of CFTR and rescue CF mutants. With our results, we will design, synthesize and test new chemicals to develop CFTR potentiators with optimal efficacy. The results of our work will accelerate the translation of discoveries in the laboratory to therapies in the clinic.

Lubiprostone induced secretion in airway submucosal glands
Grant Holder: Prof. Timothy Cox / Prof. Alan Cuthbert (PJ548)
Term/Award: 01.11.09 - 30.10.11 (24 months Project Grant) £ 25,000
Institute: University of Cambridge

Human airways contain submucosal glands that are responsible for generating most of the airway surface liquid (ASL). The fluid is passed along the airways by beating cilia until eventually it reaches the throat where it is expectorated or swallowed. Particles breathed in are trapped by the mucus floating atop the ASL, including bacteria, and eliminated from the system by the, so called, mucociliary escalator. In this way airways are maintained in a sterile condition. However, in CF the generation of the ASL is almost abolished due to the lack of functional CFTR. In consequence mucus collects in the airways, forming a breeding ground for bacteria that in the long term destroy the lung tissue. The almost universal use of antibiotics to control infection and physiotherapy to loosen and liberate the accumulated mucus in CF indicates how important the mucociliary escalator is to the normal healthy condition.
In earlier work we have shown that lubiprostone causes secretion in sheep, pig and human submucosal glands by what is apparently a non-CFTR dependent pathway. I wish now to further explore the action of lubiprostone on human CF and disease control tissues to establish its possible usefulness in CF.

Basic Science : Inflammation

Toll-like Receptor (TLR)-2 Signalling in Cystic Fibrosis Epithelium
Grant Holder: Dr B Schock (PJ547)
Term/Award: 01.06.08 - 31.05.11 (36 months Project Grant) £ 139,676
Institute: Queen's University Belfast

Improved antibiotic therapy in Cystic Fibrosis has reduced chronic infection and inflammation and its detrimental effects on the lung, resulting in increased quality of life.
However, we still do not understand how inflammation is controlled in the CF lung. Toll-Like-Receptor-2 (TLR2) is a sensor detecting invading bacteria and initiates inflammation.
In CF cells, the intracellular signal is stronger and lasts longer than in non-CF cells. In this proposal we suggest that in CF cells TLR2, which binds Pseudomonas aeruginosa, is not removed in the same timely manner as in non-CF cells. We also suggest that a protein involved in stopping inflammation, is not produced in sufficient quantities to eliminate the higher signal in CF cells. Both events leave the cell in a pro-inflammatory state for a longer time.
We wish to investigate how cells can eliminate bacteria and the mechanism of the prolonged signalling using immortalised CF and non-CF cell lines and then confirm our findings in cells grown from nasal brushings of CF patients and controls.
The results of this research will help to understand processes that regulate infection and inflammation and will assist in developing new therapies to combat chronic inflammation in CF airways.

Primary bronchial epithelial cell culture from people with cystic fibrosis (CF) - a model to study CF lung disease
Grant Holder: Dr Malcolm Brodlie (MRC 001 - Joint MRC Clinical Research Training Fellowship)
Term/Award: 01.09.08 - 31.08.10 (24 months Fellowship Award) £132,084
Institute: Newcastle University

Over 7000 people have cystic fibrosis (CF) in the United Kingdom making it the most common lifelimiting inherited disease. Death and illness in CF are largely due to progressive lung disease. The disease is characterised by severe inflammation, particularly involving neutrophilic pus cells, and structural airway damage.
Neutrophilic inflammation is one of the earliest findings in CF occurring in young children prior to obvious infection. Interleukin(IL)-17, a chemical mediator produced by the body, has attracted great interest recently as a driver of neutrophil-pus cells in a range of inflammatory diseases. In CF there is evidence that concentrations of IL-17 rise in sputum when patients become unwell.
We are the first group in Europe to establish the invaluable experimental resource of culturing cells from the lungs of actual people with CF at the time of transplantation. The first studies using our new model of CF lung disease will focus on the role of IL-17. An improved understanding of the inflammatory process may lead to new treatments capable of alleviating the inflammation and lung damage that is such a problem in CF.

Examination of pro-inflammatory response of CF nasal epithelial cells to yeasts and filamentous fungi isolated from the sputum of CF patients
Grant Holder: Prof JE Moore (PJ546)
Term/Award: 04.05.09 - 03.11.10 (12 months Project Grant) £ 54,280
Institute: Belfast City Hospital

The lungs of patients with cystic fibrosis often have bacterial infections. However, we have found that they also contain fungi. We want to know whether these fungi can activate the cells lining the airways (epithelial cells) and cause them to release biologically active molecules (mediators).
Our first series of experiments will use epithelial cell lines (both control and cystic fibrosis) and we will test the effect of four yeasts and mould organisms for various periods of time. We will check that these fungal preparations are not killing our cells.

Having established the best concentrations and times with the cell lines, we will test them using cells cultured from nasal brushings of patients with cystic fibrosis and age and sex matched healthy volunteers. These cultured epithelial cells are a model of the interactions between the fungi and the airway epithelium.

If we find that fungi can stimulate airway epithelial cells to release their mediators, then there are opportunities to use other drugs to combat the inflammatory reactions that these fungi cause. This proposed work is novel, as very few people have examined the importance of fungi in the lungs of CF patients and most attention has focused on bacteria.

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