Idiopathic pulmonary fibrosis is a disease associated with critically short telomeres, and it currently lacks a reliable and effective treatment. Researchers at the Telomere and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) have cured the disease in mice using telomerase therapy to lengthen short telomeres.
A proof of concept for an effective treatment against pulmonary fibrosis
The authors of this study have stated that this is a “proof of concept that telomerase activation represents an effective treatment against pulmonary fibrosis” in their publication.
Telomere attrition is one of the hallmarks of aging, and as lead author Dr. Maria Blasco suggests, “this is the first time that pulmonary fibrosis has been treated as an age-related disease, looking for rejuvenating the affected tissues”.
The study results suggest a potential and effective way to treat pulmonary fibrosis, which currently has no viable treatment solution. The current approved treatments do not cure the disease; they only target the consequences and not the cause of fibrosis, which is an aging process itself.
This new therapy is based on addressing the molecular cause of pulmonary fibrosis by introducing the telomerase enzyme into the damaged lung tissue and thus lengthening critically short telomeres.
What are telomeres?
We discuss in detail what telomeres are and how they are one of the causes of aging here, but in summary, telomeres are protective cap-like structures that sit on the ends of each chromosome and protect the integrity of the chromosome during cell division. Telomeres are only able to confer this protective function if they are long enough, and when they become too short, the cell ceases dividing and no longer contributes to tissue regeneration.
Short telomeres are one of the hallmarks of aging, and they increase in number as we get older; cells divide more, and thus more telomeres become critically short. This also happens in a number of diseases, including pulmonary fibrosis. In lung fibrosis, the lung tissue increasingly develops fibrotic scar tissue rather than healthy lung tissue, resulting in a loss of respiratory capacity.
While environmental factors play a key role in the development of pulmonary fibrosis, there must be telomeric damage for the disease to manifest. Patients with this disease have critically short telomeres regardless of whether the condition is inherited or not. The reason why scar tissue (which leads to fibrosis) increases as we age is most likely that when telomeres become too short, the cell initiates an inferior repair program.
A superior mouse model of fibrosis
The research team has spent five years developing an animal model that closely emulates the human disease. Before this, the most common model involved the application of the cancer drug bleomycin, which induced damage in the mouse lungs to approximate the environmental damage that initiates fibrosis. Unfortunately, this method is flawed; the animals recover from the damage in a few weeks, and there is no telomeric damage, making it a poor model of the disease.
The researchers at CNIO were looking for something better than this; they wanted something in which the environmental damage also caused shortened telomeres, as happens in the actual disease in humans. In 2015, they were successful and created the first mouse model of idiopathic pulmonary fibrosis.
This new study demonstrates that by activating the telomerase enzyme, telomeres are lengthened in lung tissue, which could be an effective therapy to combat pulmonary fibrosis in humans. The researchers observed that within three weeks of therapy, the sick animals showed improved lung function, reduced inflammation and less fibrotic tissue. Two months after the treatment, the fibrosis had significantly improved or even disappeared.
How they did it
The therapy involved introducing the telomerase gene into the lung cells via gene therapy. Dr. Blaso and her team are pioneers of AAV based telomerase therapy and, in prior studies, increased mouse lifespan using this technique . The research team used a modified virus that is harmless to humans (known as a vector) to deliver a copy of the telomerase gene to the target cells via injection. It is also important to note that the mice in this study received just one treatment to produce these results.
The researchers observed that telomerase gene therapy reverses the fibrotic tissue formation process in mice; this suggests that it could also be effective in humans as a therapy for treating fibrosis. The work was conducted in collaboration with gene therapy expert Fàtima Bosch from the Autonomous University of Barcelona.
Additionally, the researchers have obtained positive results for treating heart infarctions, aplastic anemia, and now pulmonary fibrosis using telomerase therapy. The next steps will be to work with Fàtima Bosch and Francisco Fernández-Avilés, Head of the Cardiology Service at the Hospital General Universitario Gregorio Marañón, to bring telomerase therapy closer to human trials. While human trials are still some years away, they are currently creating vectors for human therapy for when it does reach the clinic.
Telomerase therapy has long held promise for treating many of the diseases of aging, and this is yet more vindication of this. Once again, we see the potential of treating multiple diseases at once by targeting the underlying aging processes that are driving them.
While it will likely be some years before this is tested in humans, we are now within striking distance of having properly designed human clinical trials conducted by credible researchers. Once these trials are underway and the data starts coming in, we may finally have firm conclusions on the role of telomeres in aging and settle the debate on the matter once and for all.
 Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres. Maria Blasco, Juan Manuel Povedano, Paula Martinez, Rosa Serrano, Agueda Tejera, Gonzalo Gomez, Maria Bobadilla, Juana Maria Flores and Fatima Bosch (eLife 2018). DOI: 10.7554/eLife.31299
 López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
 Mice with pulmonary fibrosis driven by telomere dysfunction. Juan M. Povedano, Paula Martinez, Juana M. Flores, Francisca Mulero, Maria A. Blasco. Cell Reports (2015). doi: 10.1016/j.celrep.2015.06.028
 de Jesus, B. B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO molecular medicine, 4(8), 691-704.