CNIO (Spanish National Cancer Research Centre) researchers cure lung fibrosis in mice with a gene th
Idiopathic pulmonary fibrosis is a potentially lethal disease associated with the presence of critically short telomeres, currently lacking effective treatment. The Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) has succeeded in curing this disease in mice using a gene therapy that lengthens the telomeres. This work constitutes a "proof of concept that telomerase activation represents an effective treatment against pulmonary fibrosis," the authors write in their publication in the journal eLife. Given that telomere shortening is also an indicator of organism ageing, Maria A. Blasco, lead author of the paper, points out that "this is the first time that pulmonary fibrosis has been treated as an age-related disease, looking for rejuvenating the affected tissues".
"The most relevant aspect of our work is that it suggests a potentially viable and effective solution to a real clinical problem, pulmonary fibrosis, for which there is still no treatment," says Paula Martínez, co-first author of the paper. "The only approved treatments for pulmonary fibrosis up-to-date have no curative effects, as they target a symptom and not the cause of fibrosis. Our therapy is based on correcting the molecular cause of pulmonary fibrosis in patients with short telomeres, introducing into the cells of damaged lung tissue the only enzyme capable of lengthening telomeres, telomerase. "
Telomeres are protein structures located at the ends of each chromosome; like caps, they protect the integrity of the chromosome when the cell divides. But telomeres only fulfill their protective function if they are long enough; when they shorten too much, the damaged cells cease to divide preventing tissue regeneration. Short telomeres are associated with ageing -as age increases, cells accumulate more divisions and more telomeric shortening- and also with several diseases. Pulmonary fibrosis, which affects around 8,000 people in Spain, is one of them.
In lung fibrosis, the lung tissue develops scars that cause a progressive loss of respiratory capacity. Environmental toxins play an important role in its origin, but it is known that there must also be telomeric damage for the disease to appear. Patients with pulmonary fibrosis have short telomeres whether the disease is hereditary -it runs into the family- or not. The most likely explanation is that when the telomeres become too short, the damaged cell activates a 'repair program' that induces scar formation that leads to fibrosis.
The best animal model available
The CNIO Telomere and Telomerase Group, led by Blasco, decided to address the problem about five years ago, starting with the development of an animal model that faithfully reproduces the human disease. The most widely used model until then was to apply bleomycin into the mouse lungs to induce damage, in an attempt to reproduce the environmental insult. However, in these animals the disease goes into remission in a few weeks and there is not telomere shortening.
The CNIO researchers sought after a mouse model in which the environmental damage synergized to that produced by short telomeres, that is what happens in human pulmonary fibrosis. They succeeded in 2015, when they already indicated their next goal in their research work: "This is an essential model to test therapeutic strategies based on the activation of telomerase [the enzyme that repairs the telomeres]", they wrote in the journal Cell Reports.
Their current publication shows that activating the telomerase enzyme to lengthen the telomeres in the lung tissue may constitute an effective therapeutic strategy to treat human pulmonary fibrosis. It has proven so in mice. Only three weeks after treatment, the sick animals "showed improved lung function and less inflammation and fibrosis" -the authors write in eLife-; two months after the treatment, the fibrosis had "improved or disappeared".
A genetic driver