A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin

Area of Science:

• Biochemistry
• Dermatology
• Molecular Biology

Background:

• Fibrosis, characterized by excessive extracellular matrix deposition, affects multiple organs, including skin.
• MicroRNA-29 (miR-29) is a known antifibrotic regulator, but its therapeutic potential in skin fibrosis remains largely unexplored.
• Downregulation of miR-29 is observed in various fibrotic conditions, suggesting its role in disease pathogenesis.

Purpose of the Study:

• To identify and validate miR-29 pharmacodynamic biomarkers in mouse skin.
• To assess the cross-species conservation of these biomarkers.
• To evaluate the antifibrotic activity of a miR-29b mimic (remlarsen) in preclinical models and a human clinical trial.

Main Methods:

• Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to select miR-29 biomarkers based on gene function and mRNA expression.
• Biomarker expression was analyzed in response to remlarsen and a miR-29 inhibitor in mouse, rat, and rabbit skin wounds, as well as human skin fibroblasts.
• A double-blinded, placebo-randomized, within-subject controlled clinical trial assessed remlarsen's safety and pharmacodynamic effects in healthy volunteers.

Main Results:

• Identified conserved biomarkers, including collagens and other miR-29 targets, regulated by remlarsen across species.
• Demonstrated that remlarsen repressed collagen expression and fibroplasia in preclinical skin wound models.
• Clinical trial results showed remlarsen effectively reduced collagen expression and fibroplasia in human skin wounds, confirming its mechanism of action.

Conclusions:

• Remlarsen effectively regulates miR-29 targets in skin across multiple species.
• Clinical data support remlarsen's antifibrotic activity, demonstrating proof-of-mechanism in human subjects.
• Remlarsen holds potential as a therapeutic agent for preventing fibrotic scars and treating cutaneous fibrotic diseases like scleroderma.