CNIO researchers cure lung fibrosis in mice with a gene therapy that lengthens telomeres


Mammalian telomeres are protective
structures at the ends of chromosomes. The enzyme telomerase, composed of two subunits, the telomerase reverse transcriptase and the RNA component, is
used as a template for the de novo addition of telomeric repeats to
chromosome ends. Adult tissues, including the stem cell compartments, do not have
sufficient telomerase activity to compensate for the progressive telomere
shortening associated with cell division throughout lifespan. When telomeres reach
a critically short length, this triggers activation of a persistent DNA damage
response at telomeres and the subsequent induction of cellular senescence or
apoptosis. Idiopathic pulmonary fibrosis, a fatal lung disease characterized by
fibrotic foci and inflammatory infiltrates, is a telomere syndrome
associated with premature telomere shortening in humans. In spite of its
prevalence, this condition is still a life-threatening degenerative lung
disease, with few available therapeutic options. An important limitation to the
development of new therapeutic strategies has been the lack of
appropriate pre-clinical mouse models. We recently demonstrated that treatment
with low doses of bleomycin, which normally do not lead to pulmonary
fibrosis in wild-type mice, however, results in full-blown progressive
pulmonary fibrosis in telomerase deficient mice. In this study, we used a
telomerase reverse transcriptase 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. Our findings demonstrate that
telomerase reverse transcriptase treatment significantly improves
pulmonary function, decreases inflammation, and accelerates fiber
disappearance in fibrotic lungs as early as three weeks after viral treatment,
resulting in a more rapid improvement or disappearance of the fibrosis. At the
molecular level, this treatment results in telomere elongation and increased
proliferation of alveolar type II cells, also significantly decreasing DNA damage,
apoptosis, and senescence in these cells. Further supporting these findings,
telomerase treatment induces gene expression changes indicative of
increased proliferation, lower inflammation, and decreased fibrosis in
isolated alveolar type II cells. We provide a proof-of-principle that
telomerase activation may represent an effective treatment for pulmonary
fibrosis provoked or associated with short telomeres.

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