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

MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of...

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Vydáno v:Journal of investigative dermatology Ročník 139; číslo 5; s. 1073
Hlavní autoři: Gallant-Behm, Corrie L, Piper, Joseph, Lynch, Joshua M, Seto, Anita G, Hong, Seok Jong, Mustoe, Thomas A, Maari, Catherine, Pestano, Linda A, Dalby, Christina M, Jackson, Aimee L, Rubin, Paul, Marshall, William S
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.05.2019
Témata:
Animals
Biopsy, Needle
Disease Models, Animal
Extracellular Matrix - drug effects
Extracellular Matrix - metabolism
Fibrosis - genetics
Fibrosis - pathology
Gene Expression Regulation
Humans
Immunohistochemistry
Mice
MicroRNAs - genetics
MicroRNAs - pharmacology
Prospective Studies
Skin Diseases - drug therapy
Skin Diseases - genetics
Skin Diseases - pathology
Treatment Outcome
ISSN:1523-1747, 1523-1747
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Popis
Shrnutí:MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction. Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat, and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma.
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ISSN:1523-1747
1523-1747
DOI:10.1016/j.jid.2018.11.007