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This research investigates the role of telomerase reactivation to mitigate cellular aging and fibrosis in human lung tissue.

May 20, 2026

B19-05 Telomerase ModRNA Therapy Attenuates Senescence and Fibrosis in Human Precision-Cut Lung Slices (PCLS)

Key Points

This research investigates the role of telomerase reactivation to mitigate cellular aging and fibrosis in human lung tissue.
Engineered modRNA encoding hTERT was tested in vitro on human ATII cells and precision-cut lung slices from fibrosis patients.
Cytokine release was measured by ELISA, gene expression assessed via NGS, and senescence evaluated using β-galactosidase activity.
Circular RNA constructs were compared for sustained telomerase activation.
ModRNA hTERT significantly increased telomerase activity and hTERT expression in lung cells, promoting telomere elongation.
Sixty-one senescence-related genes were differentially expressed in fibrotic versus non-fibrotic lung tissues.
Treatment with modRNA hTERT lowered inflammation and fibrosis markers (IL-6, IL-8, TGFβ, COL1A1) while maintaining tissue viability.

Abstract

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options and a median survival of 4-6 years. Telomere shortening and alveolar type II (ATII) cell senescence are key drivers of epithelial dysfunction and fibrogenesis. Given the central role of telomerase in preserving telomere integrity, transient telomerase reactivation may offer a safe and effective strategy to restore epithelial regeneration and attenuate fibrosis. Methods A chemically modified mRNA (modRNA) encoding human telomerase reverse transcriptase (hTERT) was engineered with optimized untranslated regions, a segmented poly(A) tail, and N1-methylpseudouridine to improve stability and reduce immunogenicity. Biological activity was assessed in vitro (MRC-5 ; primary human ATII cells), and precision-cut lung slices from end-stage pulmonary fibrosis patients (PF-PCLS). Cytokine release was quantified by ELISA, gene expression was analyzed by next-generation sequencing (NGS), and senescence was evaluated via β-galactosidase (β-Gal) activity. Results Transfection with modRNA hTERT induced strong, dose-dependent telomerase activation and elevated hTERT expression in MRC-5 and ATII cells, accompanied by telomere elongation, increased proliferation, and reduced DNA damage. Transcriptomic profiling of human PCLS identified 61 differentially expressed senescence-associated genes (38 up- and 23 downregulated) in PF versus non-PF tissue. In fibrotic PCLS, senescence-associated β-galactosidase (SA-β-gal) activity and key senescence and fibrosis markers remained detectable over 14 days in culture with significant reduction following Dasatinib/Quercetin reference treatment. Remarkably, administration of modRNA hTERT significantly reduced senescence markers (SA-β-gal), pro-inflammatory cytokines (IL-6, IL-8), and profibrotic mediators (TGFβ, COL1A1) without impairing tissue viability. Finally, a circular, exonuclease-resistant hTERT RNA construct was tested to extend expression and telomerase activation. Circular RNA hTERT achieved prolonged expression and sustained telomerase activity compared with the linear construct in vitro as well as in PF-PCLS. Conclusion These findings provide the first evidence that transient hTERT reactivation via modRNA can rejuvenate ATII cell function and suppress senescence-associated inflammation and fibrosis in human PF tissue. ModRNA and circular RNA hTERT represent promising RNA-based approaches to safely target telomere dysfunction and cellular aging in fibrotic lung disease. This abstract is funded by: none

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Cite This Study

Hesse et al. (Fri,) studied this question.

synapsesocial.com/papers/6a0d50dcf03e14405aa9cfe7 https://doi.org/https://doi.org/10.1093/ajrccm/aamag162.2436

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