Therapeutic effects of telomerase in mice with pulmonary fibrosis

40 Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory 41 infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and 42 sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic 43 effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short 44 telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated 45 mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral 46 treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV947 Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower 48 DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms 49 downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that 50 telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or 51 associated with short telomeres. 52 53