The Innovation Hub programme is designated as a series of strategic partnerships between the Cystic Fibrosis Trust and academic institutions, with shared goals, shared investment and shared governance. The aim is to provide a platform for exploring experimental medicine, to create a step-change in research to solve key issues in cystic fibrosis (CF).
The focus of the Innovation Hub based at the University of Cambridge is in the area of lung health.
The aim of the Cambridge Innovation Hub is to harness multidisciplinary world-class research to accelerate progress towards preventing lung damage in CF and the subsequent loss of lung function. Specifically, it is concentrating on three areas of research to improve lung health: to develop better antibiotics and anti-inflammatories, to predict when exacerbations are likely to happen and what causes them, and to look at ways to repair existing lung damage.
It’s a five-year programme that began in 2018. The Cystic Fibrosis Trust aims to raise £5 million over the next five years for the Innovation Hub, which the University of Cambridge has already committed to match pound for pound to £5 million.
Lung damage in CF is caused by the recurrent cycle of bacterial infection and inflammation, which in turn leads to progressive lung damage and loss of lung function.
People with CF are affected by their condition in different ways, and as new precision medicines become available, this will continue to change from individual to individual. However, these medicines will not be able to reverse existing lung damage, which is what makes the lungs more prone to infection.
The sudden worsening, or flare up, of infection and inflammation, known as a lung exacerbation, is what causes lung damage in cystic fibrosis. Exacerbations can be hard to predict, and their cause is unknown. A detailed understanding of the underlying biology of exacerbations would make a significant impact on the quality of life of people with CF by refining treatments available.
Infections are currently treated by aggressive courses of antibiotics. However, effective treatment is hampered by the fact that many of the bacteria are becoming resistant to antibiotics or are already resistant.
The hub will focus on three key research areas:
- Aim 1: New approaches to treat infection and chronic lung inflammation - to develop new antibiotics to fight the bacteria carried by people with CF and to develop new, more effective ways to treat long-term inflammation in cystic fibrosis.
- Aim 2: Accurate diagnosis of, and earlier intervention for, lung exacerbations - to apply machine-learning analysis to a range of data sources from clinical home monitoring, to production and analysis of large biomarker datasets to predict and diagnose exacerbations.
- Aim 3: Developing regenerative medicine approaches to treatment - to use stem cell and gene editing technology to create human lung cells in a dish. These will be used to create new, more accurate ways to test new drugs in the lab and to develop a therapy to repair damaged lung cells.
To achieve these aims the Innovation Hub will bring together global experts from medical sciences and other fields such as molecular biology, genetics, drug discovery, computer science and regenerative medicine.’.
The day-to-day management of these key research areas within the Innovation Hub are the responsibility of the Academic Leads. These are Professor Andres Floto (Aims 1 and 2), Professor Julian Parkhill FRS (Aim 1), Professor Sir Tom Blundell FRS (Aim 1), Professor Chris Abell FRS (Aim 1) and Professor Ludovic Vallier (Aim 3).
Professor Andres Floto is also the Director of the Innovation Hub, overseeing the whole programme of work within it.
Find out more about the researchers leading and working within the Innovation Hub.
Professor Andres Floto, Professor Julian Parkhill, Professor Sir Tom Blundell and Professor Chris Abell are contributing to this workstream. Over-active inflammation is a major contributor to the lung damage that is responsible for almost all deaths associated with cystic fibrosis. Both CF and the infections people with CF develop can lead to inflammation, but we do not properly understand which comes first or how they interact.
Research in this workstream will investigate new ways to reduce inflammation, by developing new, more effective antibiotics and re-purposing existing anti-inflammatories that are suitable for people with cystic fibrosis.
New antibiotics: There are hundreds of different chemical reactions taking place in bacteria to help them grow and survive. Existing antibiotics target a small fraction of these. This programme of work will try to understand more about how every reaction in bacteria works (target identification), and use this information to apply innovative approaches to develop new antibiotics, such as computational chemistry to identify fragments and then fragment-based design of drugs.
The researchers will focus on developing drugs for Pseudomonas aeruginosa (P. aeruginosa) and Mycobacterium abscessus (M. abscessus), two of the most dangerous bacteria for people with cystic fibrosis. Antimicrobial resistance is a major global concern and a critical government priority, and this research could offer new hope for other multidrug-resistant infections.
New anti-inflammatory drugs: Within this workstream, research is underway to find anti-inflammatory drugs that reduce inflammation in cystic fibrosis, by adjusting the effects of the body’s immune system. The drugs need to strike a balance between allowing the body’s immune response to do its normal role - guarding against toxins (including infections) and repairing injury - and dampening down any over-reaction or uncontrolled response. In developing anti-inflammatories for people with CF, managing this balance can be particularly difficult. This is due to the long periods of time that inflammation is present, the chronic bacterial infection in the lungs and the effects of the CFTR gene (that causes CF) on inflammation. More effective, better tolerated anti-inflammatory drugs are needed.
This work is being led by Professor Andres Floto, who is actively collaborating with Dr John Winn at Cambridge-based Microsoft Research.
Improved technology has the potential to make a big difference to the lives of people living with cystic fibrosis. This improved technology ranges from internet-enabled or ‘smart’ medical equipment at home, to up-and-coming new ways for self-monitoring of health and wellbeing, through to genetic and protein-analytical techniques. Above all is the capacity to store, process and analyse the resulting vast amounts of data and to link these data sources together.
The outcomes of these analyses could mean people are less limited by their cystic fibrosis. For example, they could provide a more streamlined approach to clinical management - potentially enabling fewer visits to hospital, both as part of a person’s standard care or when they are participating in a clinical trial - more precise monitoring of clinical trials, accurate prediction (and consequently earlier treatment for) lung exacerbations and a better understanding of the underlying biology of cystic fibrosis.
This workstream will continue to explore the role of digital health and analysis of large data sets to reduce exacerbations. The aim is to develop a system that is responsive to the development of new technologies that measure physiological, biochemical and patient-reported measures of their lung health.
Here are some examples of specific projects currently underway:
Project Breathe This a service evaluation and improvement of home monitoring of CF, which will help to personalise clinic appointments around the needs of each person with CF at the time. This may by a reduction in the number of clinic appointments or a change in their focus (eg more time with a specific member of the CF team).
Machine-learning analysis of home-monitoring data The data collected through the Project Breathe study and other work will be analysed to determine more precise ways of predicting and monitoring lung exacerbations. This will enable earlier treatment, reducing lung damage. The analysis may also highlight more accurate ways of monitoring clinical trials.
Sputum biomarker analysis The researchers are also collecting and analysing sputum samples to understand the burden of infection and inflammation that leads to an exacerbation. Studying the pattern of chemicals in the samples, the researchers also hope to be able to identify a unique pattern that is characteristic of when an exacerbation is about to occur - in other words, a ‘biomarker’ of an exacerbation. This would complement the work to develop a physiological predictor of an exacerbation from the machine-learning analysis described above.
This work is being led by Professor Ludovic Vallier.
The initial goal of this workstream is to create a range of different types of human lung cells in the lab using stem-cell and gene-editing technology. The lung cells will be used both as a way of modelling the effects of new drugs, particularly drug combinations during drug development, and as a starting point for a cell therapy or lung-cell graft for people with cystic fibrosis.
Create corrected lung cells in the lab The first step to creating human lung cells to study in the lab is to obtain stem cells. Stem cells are basic cells that have the potential to turn into any cell in the body. It’s possible for researchers to create stem cells from other cell types in our bodies, such as blood cells. These types of stem cells are known as induced pluripotent stem cells, or ‘iPSCs’. Creating iPSCs from donor cells is a very difficult technique to get right in the lab.
Professor Vallier’s lab is working to create iPSCs from cells donated from people with cystic fibrosis. The iPSCs will carry the same CF-gene mutations as the donor. The iPSCs will then be to converted into a range of different types of lung cells for research, including the newly discovered ionocytes. For some of the iPSCs, gene editing to correct the mutations in the CF gene will be carried out. So, for each individual, it is possible to create cells containing the original mutation in the CFTR gene and where the mutation has been corrected.
Testing new drugs Before drugs and drug combinations are tested in people in clinical trials, it is important to be able to test new drugs for CF in the lab in a way that mimics the human lungs as closely as possible. There are many different ways of achieving this, however, few are based on cells from people with cystic fibrosis. The studies conducted as part of the Innovation Hub will achieve this. Each individual living with CF is likely to respond to drugs in a slightly different way (even if comparing two people with the same CFTR genotype). Using human lung cells for this ‘ex-vivo’ drug testing will provide the best possible way for researchers to understand these complex reactions that determine the effectiveness of new drugs.
Lung-cell grafts Currently it isn’t possible to repair lung damage that occurs in people with cystic fibrosis. One of the aims of this research is to develop methods to use stem cell-derived lung cells to create a lung cell ‘graft’. This includes preparing the lung cells to graft and investigating the best way to do a successful graft. Lung cells will be prepared using gene editing to correct the mutated CF-gene and growing enough of the right type of lung cells. For a successful graft Professor Vallier and his team need to develop a way of getting the new lung cells delivered to and working in the lining of the lungs.
By using cells from a lung-graft recipient as the starting point for the iPSCs, when the lung graft is completed there won’t be rejection as with lung transplants.
This lung cell graft is in extremely early stages of development (approximately five years from clinical trials).
The Innovation Hub also aims to maximise its local, national and international connections, harnessing the knowledge and resources of its partnerships. There are plans to develop a national network infrastructure to create new resources for cystic fibrosis research in the future.
The Cystic Fibrosis Trust is very grateful for the support shown to this project. We would especially like to thank The Robert Luff Foundation and AJN Steelstock for their ongoing and generous support, along with a number of donors, trusts and companies. To date £1.62 million has been kindly donated / pledged for the Innovation Hub.
For further information on support for the Innovation Hub please contact Beth Isherwood, Head of Philanthropy.