Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres.

Juan Manuel Povedano,Fátima Bosch,Águeda Tejera,Rosa Serrano,Gonzalo Gómez-López,Maria Bobadilla,Juana Maria Flores,Paula Martinez,Maria A Blasco

doi:10.7554/elife.31299

Abstract

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

Highlights

Mammalian telomeres are protective structures at ends of chromosomes that consist of TTAGGG repeats bound by a six-protein complex known as shelterin (Blackburn, 2001; de Lange, 2005)
We set to address whether telomerase treatment of adult mouse lungs by using AAV9-Tert vectors could effectively prevent the progression of pulmonary fibrosis provoked by damage to the lungs and the presence of short telomeres (Povedano et al, 2015), a scenario that resembles both familiar and sporadic cases of the human disease (Alder et al, 2008; Armanios, 2013; Armanios et al, 2007)
It is relevant to note that this is in contrast to the widely used mouse model of pulmonary fibrosis using a much higher dose of bleomycin (2 mg/kg body weight), which leads to pulmonary fibrosis in wild-type mice but does not recapitulate the short telomere phenotype present in human patients

Summary

Introduction

Mammalian telomeres are protective structures at ends of chromosomes that consist of TTAGGG repeats bound by a six-protein complex known as shelterin (Blackburn, 2001; de Lange, 2005). This model shows that short telomeres are at the molecular origin of pulmonary fibrosis and could represent a useful pre-clinical tool to test the challenging hypothesis of whether therapeutic strategies based on telomerase activation maybe effective in the treatment of the disease We tested this hypothesis by using a Tert based gene therapy in mice diagnosed with pulmonary fibrosis owing to treatment with low doses of the lung-damaging agent bleomycin in the context of short telomeres, a scenario that resembles pulmonary fibrosis in humans associated with short telomeres. Telomerase treatment induces gene expression changes indicative of increased proliferation, lower inflammation and decreased fibrosis in isolated ATII cells

Results

Discussion

Materials and methods