The development of personalised molecular therapies to treat disorders of surfactant protein metabolism

Nicole Shaw, André Schultz, Anthony Kicic, Steve Wilton, Sue Fletcher, Stephen Stick

Project description
Type-II pneumocytes, located in the alveoli of the lung, are responsible for the production and homeostasis of pulmonary surfactant. Mutations in specific genes related to the surfactant system such as Surfactant Protein C (SFTPC), Surfactant Protein B (SFTPB) and ATP-binding cassette subfamily A, member 3 (ABCA3) have been associated with neonatal respiratory distress and paediatric interstitial lung disease. The spectrum of lung disease varies from being rapidly fatal, to disease that slowly resolves during childhood. At present there is no effective, evidence-based treatment for congenital disorders of surfactant protein metabolism (DSPM). However, it has been proposed that antisense oligonucleotide therapy may be a viable option for improving health outcomes in a subset of patients based on their specific genetic mutation. The proposed project aims to explore the potential of this therapy to treat patients with pathogenic mutations in ABCA3 that are amenable to splice switching intervention, while establishing appropriate disease models and functional assays in order to test specifically designed antisense oligonucleotides.

Plain Language summary
Lung surfactant, produced by special lung cells, enables the air-spaces of the lung to be ready to expand at the end of the breathing cycle. Without lung surfactant, breathing requires a lot of energy and becomes very difficult. Certain molecules involved in the production of surfactant in lung cells and secretion into the air-spaces of the lung are required for the surfactant system to work properly.  Inherited defects affecting these molecules can cause severe lung disease in infants and children, which can result in death. Survivors often spend much of their early life going in and out of hospital. At present, there are very few treatment options for patients with the disease. This project aims to investigate the possibility of using specific small molecule medicines to improve the function of molecules involved in the surfactant system for people with the inherited disorder. The small molecule medicines act by changing the way that the defective genes work.  Changing the way that the genes work, results in the generation of molecules with a different structure and modifies the way that the molecule functions. This may lead to increased surfactant production.