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

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.

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.