MICA: Defining Endotypes of Pulmonary Fibrosis by Understanding the Functional Consequences of Known, and Novel, Genetic Associations with Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive lung condition characterised by scarring (fibrosis) of the lungs. This scarring deforms the lungs and reduces the ability of the lungs to take in oxygen, which causes a person to feel breathless and cough. It is not clear why some people develop IPF, but people with IPF often progress quickly to death and there is no cure. Each year 6000 people in the UK die of IPF, more than deaths from most cancers, and more than ovarian, cervical and thyroid cancers combined. This makes IPF an important disease to research.

It is currently thought that genetic changes in the cells that line the lung (epithelial cells) make them susceptible to injury and scar formation, although, how these genetic changes promote scarring remains unknown. The main feature of lung scarring is that the lungs become small and stiff due to the abnormally high activity of cells that make scar tissue.

There are broadly two types of cell responsible for scar formation: epithelial cells that line the small airways and airsacs of the lung and fibroblasts, that produce the glue that provides the scaffolding for the lung. When the lung is injured epithelial lung cells send signals to fibroblasts asking for more scaffolding to be made to help repair the lung. However, if the lining cells are genetically reprogrammed to ask the fibroblasts to build excessive of abnormal scaffolding in response to injury it promotes scarring that make the lungs stiff, and contract, making the lungs small.

Mechanical forces that occur when the lung stretches during breathing, or when the lungs become becomes stiff in IPF, are important in the development of fibrosis. In IPF, scarring begins at the edges and bottom of the lungs, areas that are being stretched the most. Our research has shown that a number the genes associated with IPF affects pathways involved when epithelial cells or fibroblasts are stretched. Furthermore, when fibroblasts grow in stiff surroundings, such as that within a scarred lung, they become even more active and produce more scar tissue. However, how mechanical forces affect cells with genetic changes found in IPF, or how the genetic changes affect the signals the that epithelial cells and fibroblasts send remains unknown. Importantly, whether the genes and cellular signals reflect sub-types of IPF that might respond better, or worse, to the current anti-fibrotic drugs is not known

This programme of work will use a number of distinct but complementary scientific techniques including genetics, cell and molecular biology, and pre-clinical modelling to investigate how the epithelial lining cells and fibroblasts go wrong during the development of lung fibrosis and whether they can be specifically targeted by anti-fibrotic drugs. The programme will focus on a key molecular pathway, the small G protein signalling pathway, which regulates these cells' mechanical properties. The aim of this project is to understand 1) precisely map the genetic signals we have already observed, and identify new genetic signals so we can accurately manipulate these genes in test tube experiments 2) define how the genetic signals in epithelial lining cells effect RhoA and Rac function and in turn how this alters the chemical messengers generated by these cells 3) understand how genetic signals in fibrblasts of lead to altered RhoA and Rac activity and the effect this has on the fibrotic potential of these cells 4) define whether these abnormalities leads to different effects in these cells in a way that can be exploited to personalise therapy to ensure the right patient gets the right treatment at the right time.

The work will be undertaken by several academic investigators in partnership with Galecto Biotech, Nordic Bioscience and Redex Pharma to give the programme the best chance of leading to a new treatment for IPF.

Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with no cure. It results from injury to genetically susceptible epithelium leading to activation of fibroblasts. Preliminary data have identified two distinct groups of prognostic biomarkers that may reflect distinct endotypes originating from either epithelial cells or fibroblasts. Our published, and preliminary, genomic data have identified a number of genes associated with mechanotransduction pathways in both cell types. Also, prior work from a number of groups has shown these pathways to be central to IPF, but their molecular details differ in these two cell types. It is possible that these differing molecular pathways may reflect endotypes that could be targeted in a drug dependant manner leading us to this hypothesis:

Diverse genetic signals in mechanotransduction pathways promote the development of targetable epithelial and mesenchymal endotypes of pulmonary fibrosis.

We will test this hypothesis using a range of scientific approaches across three distinct but interacting work packages (WPs).
WP1: Integration of large genetic datasets to fine-map and characterise the likely causal effects of known and new genetic association signals for pulmonary fibrosis and understand the epigenetic regulation of these signals.
WP2: A range of molecular techniques will be used to manipulate genes, and their function, in primary epithelial cells and fibroblasts to understand the consequences of the genetic signals that we have identified and determine whether they can be selectively targeted with available and novel anti-fibrotics.
WP3: Murine and human tissue models will be used to determine whether the genes and molecular pathways identified in WP1 and 2 lead to differential endotypic responses to anti-fibrotics in whole tissue and organ systems.
We will integrate the data from all three WPs to develop translational strategies to therapeutically target endotypes of pulmonary fibrosis in the clinic.

Social impact: Currently, treatment options for IPF are limited. This programme will build on our knowledge of pulmonary fibrosis and create new understanding of the initiation and progression of IPF. This will lead to new, faster and cheaper approaches to diagnosis and treatment, improve prognosis and enhance quality of life. New approaches to managing and treating IPF will reduce costs to the NHS and free-up recourses that can be invested into other areas of healthcare. Additionally, the insight delivered from this programme of work will inform and improve government policy and ensure patients are receiving care based on the most relevant and up-to-date knowledge.

Government and policymakers: This collaboration will provide data on new ways of understanding disease heterogeneity and targeting therapy in IPF. Our findings will ultimately provide data to inform new guideline development for the treatment of IPF by organisations such as NICE leading to economic impacts.

Economic impact: Treating pulmonary fibrosis causes significant economic pressure. The cost of antifibrotics in the UK is high (£26,000/patient/year), and there are further costs associated with drug monitoring and managing side effects. NICE has approved anti-fibrotic drugs for patients with advanced IPF based on lung function criteria (Forced Vital Capacity between 50 and 80% predicted), but the best time to start therapy is not known. This project will identify new endotypes of fibrosis which will enable therapy to be prescribed in a more targeted way so the right patient receives the right drug at the right time. This will lead to reduced prescription costs, reduced adverse effects and a prolonged health-span. Furthermore, this program may identify novel therapeutic targets to treat IPF which will further reduce the severity of the condition and costs of treatment. Identification of new diagnostic, prognostic and therapeutic targets will generate new wealth for the UK through intellectual property, and commercialisation of novel therapies. This will stimulate further UK investment opportunities to create new UK companies, jobs and infrastructure. The combined effect of reducing economic burden while creating new knowledge will have a positive economic impact.

Knowledge: We will advance our knowledge of pulmonary fibrosis by creating a data platform using human and murine data to provide a more accurate assessment of drug targets, and the efficacy and safety of novel therapeutic agents. These platforms will then inform reverse translation to assess these endotypes in murine models of fibrosis which will improve modelling accuracy. Our platforms will lift the burden placed on the use of animal models for respiratory research and improve our knowledge on how in-vitro and ex-vivo models can be constructed and exploited to gain accurate information. We will also generate unique techniques relating to manipulation of these modelling platforms.

People: Currently there are no other research groups in the UK, and few in the world that have the combined knowledge and expertise to propose this type of work. This proposal will provide a unique opportunity to train UK based researchers, both directly and indirectly involved with this project and expand this area of expertise within the UK. This will ensure a continued production of researchers with the necessary skills to further utilise, expand and adapt these platforms for their own use within the respiratory research field with added benefits to the third sector through increased profile of IPF.

The third sector: Charities will benefit through increased profile of IPF research and the generation of new knowledge. This will inform strategy for patient groups and charities such as Action for Pulmonary Fibrosis. Research and education are major objectives for charities and new knowledge will accelerate IPF research and will be used to generate further interest in charities and their objectives.