Telomerase <scp>modRNA</scp> Offers a Novel <scp>RNA</scp> ‐Based Approach to Treat Human Pulmonary Fibrosis

Pulmonary Fibrosis (PF) is a life-threatening illness that is characterized by progressive scarring in the lung interstitium. There is an urgent need for new PF therapies because current treatments only slow down the progression of fibrosis, and the median life expectancy post-diagnosis is only 4-6 years. Since PF patients frequently exhibit telomere attrition, overexpressing telomerase, the enzyme responsible for synthesizing telomeres, represents a compelling therapeutic option. In this study, we in vitro transcribed human telomerase reverse transcriptase (hTERT) mRNA using modified nucleosides (modRNA). ModRNA hTERT treatment led to transient activation of telomerase activity in a dose-dependent manner in MRC-5 cells and, importantly, in primary human alveolar type II pneumocytes. Consequently, the proliferative capacity was increased, concomitant with reduced DNA damage and elongated telomere length. Notably, the induction of cellular immune response was only detectable at the highest modRNA concentration and returned to normal levels within 48 h. Next, we demonstrated that circularized, exonuclease-resistant modRNA hTERT extended the transient expression profile, which may be clinically advantageous. Finally, we provided therapeutic proof of concept in organotypic 3D ex vivo human precision-cut lung slices derived from end-stage PF patients. Intriguingly, a single modRNA hTERT treatment inhibited senescence, as indicated by significantly lower levels of senescence-associated β-galactosidase. Pro-inflammatory markers (IL6 and IL8) and, concurrently, the key fibrosis mediators TGFβ and COL1A1 were markedly reduced after modRNA and circular RNA hTERT treatment. In conclusion, the data presented herein provide initial evidence for the potential of RNA-based hTERT therapy for treating human lung fibrosis.