Surfactant protein C (SFTPC) gene mutations are amongst the most common forms of inherited disorders of surfactant metabolism as idiopathic pulmonary fibrosis (IPF). The most frequent mutation I73T results in a SP?C toxic dominant-negative form, requesting novel therapeutic approaches. Based on our previous work, we developed a new gene therapy based on Adeno-Associated Virus (AAV) vector to treat SFTPC mutation-induced IPF.

We generated an I73T knock-in transgenic mouse model with a decrease in Sftpc and mature SP-C protein expression compared to wildtype mice. They developed alveolar type 2 cell hyperplasia with pro-SP-C protein accumulation and focal airspace enlargement indicative of an emphysematous phenotype but no fibrosis, even upon aging. We applied gene replacement in these mice using an AAV?SP?C vector by single intratracheal administration. AAV-SP-C administration restored wildtype Sftpc and mature SP-C protein expression while significantly decreasing the mean linear intercept and ameliorating lung function parameters. In parallel, we developed a gene replacement + mutated version silenced therapy. AAV?miR silenced Sftpc endogenous expression and reduced proSP?C protein excess. The combined AAV-SP-C-miR led to a Sftpc endogenous expression decrease, restored wildtype Sftpc, re-expressed the mature SP?C protein without proSP-C protein significant modulation. While AAV?SP?C?miR restored the structural emphysema phenotype to WT state, functional changes were less prominent.

To conclude, the spontaneously emphysema developed in I73T mice can be reversed with a combinatorial gene therapy approach raising the possibility to treat SFTPC mutation induced IPF.