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Elife. 2018 Jan 30;7. pii: e31299. doi: 10.7554/eLife.31299.

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

Author information

1
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain.
2
Bioinformatics Core Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Centre, Madrid, Spain.
3
Roche Pharma Research and Early Development (pRED), Neuroscience, Ophthalmology and Rare Disease, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
4
Roche Partnering, EIN, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
5
Animal Surgery and Medicine Department, Faculty of Veterinary Science, Complutense University of Madrid, Madrid, Spain.
6
Centre of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Autonomous University of Barcelona, Bellaterra, Spain.
#
Contributed equally

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.

KEYWORDS:

AAV9; chromosomes; gene therapy; genes; mouse; pulmonary fibrosis; telomerase; telomeres

Conflict of interest statement

JP, PM, RS, ÁT, GG, JF, FB, MB No competing interests declared, MB is an employee for F. Hoffmann-La Roche Ltd, and the author declares no other competing financial interests

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