MICA: Investigating mRNA encoded growth factor to promote epithelial repair in pulmonary fibrosis.

Fibrosis of the lung is the gradual replacement of alveolar of air sacs with scar tissue that prevents the organ from carrying out efficient gas exchange and currently has no cure. Lung fibrosis can occur as a result of chronic disease such as idiopathic pulmonary fibrosis (IPF) or severe epithelial injury during respiratory infection. There are 6000 new cases of IPF each year in the UK, it is increasing in incidence and survival is only 3-5 years after diagnosis. Fibrosis remains one of the largest threats to health after recovery from COVID-19 and influenza. There is an urgent and unmet need to develop new therapies that can alter the progression of fibrosis. Repeated lung injury and an inability to repair properly play a central role in lung fibrosis, suggesting that repair processes could be important targets for therapy. Epithelial basal cells (BCs) are adult stem cells of the lung that can self-renew or differentiate to all types of lung epithelium after injury. They normally function to repair lungs efficiently, however recent studies suggest that basal cell function might be impaired in fibrosis. Further investigation is required to understand whether these cells can be manipulated to control how they function. Growth factors play an essential role in coordinating growth and regeneration of lung tissue. Fibroblast growth factor 7 (FGF7) binds specifically to FGF receptor 2-IIIb (FGFR2b) expressed only on epithelial cells including BCs to promote growth and differentiation. FGF7 has been shown to be dysregulated in lung fibrosis, as a result there is interest in supplementing FGF7 to promote repair and reduce fibrosis in the lung for disease modifying therapy. Delivery of FGF7 protein after lung injury in human and animal models has demonstrated its powerful influence on lung repair but it's use has been hindered because it must be delivered by intravenous injection which results in rapid elimination from the body, poor distribution to the lung and high toxicity. Synthetic messenger RNA (mRNA) is an emerging technology that instructs the body's own cells to produce a specific protein with transformative potential for how growth factors are applied clinically. Growth factors encoded by mRNA are being tested for heart and skin repair in humans but has never been attempted for the lung, partly due to challenges in delivery. We have previously developed materials to protect synthetic mRNA and facilitate its delivery into lung cells following nebulised delivery. This proposal will bring together our experience in mRNA delivery, with expertise in lung repair and fibrosis to investigate mRNA encoded growth factors as a novel strategy to guide lung repair after injury. In order to achieve our goal, we aim to address three key questions: 1. What is the influence of FGF7 mRNA on survival, proliferation and migration of human basal cells from normal and IPF lungs? 2. Can FGF7 mRNA promote differentiation of basal epithelial cells in human lung organoids? 3. Does local delivery of FGF7 mRNA reduce fibrosis and improve lung function following injury in a murine model? The outcomes of our research will be instrumental for the application of synthetic mRNA as a platform for protein production in the lung that could be broadly applied to different protein targets and will bring this pioneering technology closer to improving human health.