Telomere Dysfunction May Be Therapeutic Target in PF

A new report suggests that RNA-based human telomerase reverse transcriptase (hTERT) therapy might be a viable method to treat pulmonary fibrosis (PF).

The findings, which were published in Aging Cell, suggest such therapies could spark telomere expression and activity sufficient to elongate telomeres and improve the health of lung cells.¹

Corresponding author Shambhabi Chatterjee, PhD, of the Hannover Medical School, in Germany, and colleagues noted that PF is the most fatal subtype of interstitial lung disease, with a post-diagnosis survival of only 4 to 6 years.²

The authors explained that one potentially fruitful area to examine in the search for a cure is telomere dysfunction. Telomere dysfunction has been identified as a risk factor for PF and idiopathic pulmonary fibrosis (IPF). Such dysfunction is generally associated with aging, a fact that aligns with research showing that the incidence of IPF increases dramatically in populations over the age of 65. Additionally, they said there is a strong correlation between telomere length and IPF disease severity.³

The investigators therefore assessed whether addressing telomere dysfunction might also address the underlying PF.¹

“Considering that telomere shortening is a key driver and strongly associated with PF, reactivating the enzyme telomerase, which synthesizes telomere repeats, would evidently offer a powerful therapeutic approach to replenish telomeres and to mitigate cellular senescence in PF,” they wrote.

The investigators transcribed hTERT mRNA using modified nucleosides (modRNA). They then treated human primary fetal lung cells (MRC-5 cell line) with modRNA hTERT, and found that it led to transient activation of telomerase activity in a dose-dependent manner. This occurred both in MRC-5 cells and in primary human alveolar type II pneumocytes.

“Consequently, the proliferative capacity was increased concomitant with reduced DNA damage and elongated telomere length,” they wrote. “Notably, the induction of cellular immune response was only detectable at the highest modRNA concentration and returned to normal levels within 48 hours,” they explained.

Next, Chatterjee and colleagues decided to see whether they could extend the transient expression of modRNA hTERT by circularizing the in vitro transcription product to increase its stability.

“Strikingly, in contrast to modRNA hTERT, circular RNA hTERT resulted in significant telomere elongation after 96 hours of treatment,” they wrote.

To further test their hypothesis, the investigators devised a state-of-the-art organotypic model of the human lung using precision-cut lung slices (PCLS) from patients with end-stage PF.

“Intriguingly, a single modRNA hTERT treatment inhibited senescence, as indicated by significantly lower levels of senescence-associated β-galactosidase,” they wrote. The authors found that the treatment also reduced levels of the pro-inflammatory markers interleukins 6 and 8, while also curbing the fibrosis mediators TGFβ and pro-COL1A1.

In total, the authors said their findings show the biological efficacy and feasibility of hTERT in their PCLS platform setting. However, they added that because the samples were ex vivo, their viability—and thus the ability to obtain long-term findings—is limited. They said there were also other technical constraints that would make it necessary to use a variety of complementary models in order to fully assess the utility of this therapeutic strategy.

Chatterjee and colleagues said other questions remain about how best to deliver such a therapy, given the need to minimize off-topic effects.

For now, though, they said their findings support the potential of repeated modRNA-mediated hTERT therapy for PF and also raise the potential that circular RNA hTERT might offer a significant improvement on that strategy.

References

1. Ye JL, Grieger K, Lu D, et al. Telomerase modRNA offers a novel RNA-based approach to treat human pulmonary fibrosis. Aging Cell. Published online September 20, 2025. doi:10.1111/acel.70240

2. Yamazaki R, Nishiyama O, Yoshikawa K, Tohda Y, Matsumoto H. Outcome of patients who were incidentally diagnosed with idiopathic pulmonary fibrosis: How early in the disease should we identify patients?. Respir Med. 2022;201:106933. doi:10.1016/j.rmed.2022.106933

3. Duckworth A, Gibbons MA, Allen RJ, et al. Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a Mendelian randomisation study. Lancet Respir Med. 2021;9(3):285-294. doi:10.1016/S2213-2600(20)30364-7