Telomerase modRNA Offers a Novel RNA-Based Approach to Treat Human Pulmonary Fibrosis

Area of Science:

• Biochemistry
• Molecular Biology
• Pulmonary Medicine

Background:

• Pulmonary fibrosis (PF) is a progressive lung scarring disease with limited treatment options.
• Current therapies only slow fibrosis progression, with a poor median life expectancy post-diagnosis.
• Telomere attrition is common in PF patients, suggesting telomerase as a therapeutic target.

Purpose of the Study:

• To investigate the therapeutic potential of modified RNA (modRNA) encoding human telomerase reverse transcriptase (hTERT) for pulmonary fibrosis.
• To assess the effects of modRNA hTERT on lung cell proliferation, DNA damage, and telomere length.
• To evaluate the efficacy of modRNA hTERT in preclinical models of human lung fibrosis.

Main Methods:

• In vitro transcription of modified nucleoside RNA (modRNA) encoding hTERT.
• Treatment of human lung cells (MRC-5, primary alveolar type II pneumocytes) and 3D precision-cut lung slices with modRNA hTERT.
• Assessment of telomerase activity, cell proliferation, DNA damage, telomere length, senescence markers, and inflammatory/fibrosis mediators (IL6, IL8, TGFβ, COL1A1).

Main Results:

• modRNA hTERT transiently activated telomerase in lung cells, increasing proliferation and telomere length while reducing DNA damage.
• Transient immune response observed at high concentrations, returning to baseline within 48 hours.
• Therapeutic proof of concept in ex vivo PF lung slices: single modRNA hTERT treatment reduced senescence, pro-inflammatory markers, and key fibrosis mediators.

Conclusions:

• RNA-based hTERT therapy, using modRNA or circular RNA, demonstrates potential for treating human lung fibrosis.
• modRNA hTERT effectively targets key pathological mechanisms in PF, including senescence and fibrosis.
• Further development of RNA-based hTERT strategies is warranted for PF therapeutic applications.