Gene Therapy Halts Age-related Lung Fibrosis, Mouse Study Shows

A gene therapy that lengthens the life of lung cells can halt scarring and help sustain lung regeneration in a mouse model of age-related pulmonary fibrosis, a new study shows.

The study, “Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging,” was published in the Journal of Cell Biology.

Evidence suggests that the lungs of idiopathic pulmonary fibrosis (IPF) patients fail to regenerate since the cells involved in lung regeneration have shorter telomeres, the protective caps at the end of chromosomes. In fact, between 8% and 15% of familial IPF cases are associated with mutations in the gene for telomerase — the enzyme that repairs telomeres — or in telomere-protective proteins.

Even in the absence of mutations in telomerase or telomere-related genes, IPF patients are reported to have shorter telomeres than healthy individuals.

Researchers at the Spanish National Cancer Research Centre (CNIO) previously developed a gene therapy to introduce the telomerase gene into lung cells with the help of a virus (AAV9 viral vector), which was modified to cause no harm to humans.

The results showed that activating telomerase improved lung function and lessened inflammation and fibrosis in a mouse model of PF in which fibrosis was induced by short telomeres. Mice received one injection of the gene therapy. After eight weeks of treatment, fibrosis continued to be resolved and even disappeared.

In the new study, researchers tested the same gene therapy in a mouse model with age-related fibrosis.

The team first showed that aging led to telomere shortening and reduced the proliferation ability of alveolar type 2 and club cells, two types of cells important for lung regeneration.

Mice genetically engineered to lack telomerase showed a reduction of both cell types, alveolar type 2 and club cells, at much younger ages and equivalent to that seen in old, normal (wild-type) mice.

Aging led to the activation of fibroblasts — the cells responsible for the synthesis and buildup of scar tissue (fibrosis) — and to collagen deposition in the lungs of mice, both in the ones lacking telomerase and in wild-type mice. However, this occurred earlier in mice without telomerase.

With aging, alveolar type 2 cells stop working properly. These cells are not only important for regeneration but also for the normal function of the lungs, which requires the action of secreting surfactant proteins whose release is impaired by aging.

“We have observed a very clear relation between telomere status in type II pneumocytes, pulmonary surfactant production and fibrosis development in animals,” Jesús Pérez-Gil, PhD, at the Complutense University of Madrid, an author of the study, said in a CNIO press release.

“Lung tissue must expand when we breathe in, six to ten times per minute, which means a great deal of physical effort. Pulmonary surfactant plays an important role in lubricating lung tissue, retaining its elasticity, and reducing the amount of work required to expand and contract it,” Pérez-Gil said. “If type II pneumocytes fail to regenerate, the surfactant is not produced, which results in lung stiffness and fibrosis.”

Treatment of telomerase-deficient mice with the telomerase gene therapy partially restored the surfactant protein’s activity.

Moreover, telomerase gene therapy led to a significant increase in the numbers of alveolar type 2 and club cells in both wild-type and telomerase-deficient mice, an important stage for lung recovery. The gene therapy also significantly reduced the numbers of fibroblasts and their activation in the animal’s lungs.

Mice treated with the gene therapy also showed a reduction in pro-inflammatory factors.

“The telomerase-activating gene therapy prevented the development of fibrosis in all mice, including the ones without genetic alterations that only underwent physiological ageing,” said Maria Blasco, PhD, the study’s lead author.

“With respect to humans, our results indicate that it may be possible to devise a treatment to prevent the development of pulmonary fibrosis associated with ageing,” Blasco added.

Overall, “these findings suggest that short telomeres associated with physiological aging are at the origin of IPF and that a potential treatment for IPF based on telomerase activation would be of interest not only for patients with telomerase mutations but also for sporadic cases of IPF associated with physiological aging,” the researchers concluded.