Gene Editing Strategies for the Treatment of Surfactant Protein C Deficiency (360G-Wellcome-337136_Z_25_Z)

Surfactant Protein C (SP-C), encoded by the SFTPC gene, is a critical component of pulmonary surfactant, produced in alveolar epithelial cells to reduce surface tension and prevent alveolar collapse. Mutations in SFTPC cause SP-C deficiency, a rare genetic lung disease with highly variable penetrance, ranging from lethal neonatal respiratory failure to milder respiratory symptoms in adulthood. With no cure beyond lung transplantation, which often succumbs to rejection, there is an urgent need for novel therapies addressing the underlying genetic cause. This project aims to develop gene therapies for SP-C deficiency via two strategies: precise and mutation-agnostic. First, I will use advanced base and prime editing strategies to correct the most common variant, I73T, found in ~30% of patients. Secondly, mutation-agnostic methods such as HITI, eePASSIGE, or STITCHR will be applied to replace the mutant gene with a healthy copy, regardless of genotype. Finally, I will uncover additional pathogenic mutations contributing to disease progression and variable penetrance by analysing data from the 100,000 Genomes Project. This insight will inform personalised therapies, targeting both SFTPC and modifier genes, and will prioritise patients most in need of treatment, offering transformative potential for those affected by this life-limiting disorder.