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

Autor:	Gallant-Behm CL; miRagen Therapeutics, Inc, Boulder, Colorado, USA. Electronic address: cbehm@miragen.com., Piper J; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Lynch JM; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Seto AG; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Hong SJ; Division of Surgery, Northwestern University, Chicago, Illinois, USA., Mustoe TA; Division of Surgery, Northwestern University, Chicago, Illinois, USA., Maari C; Innovaderm Research, Montreal, Quebec, Canada., Pestano LA; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Dalby CM; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Jackson AL; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Rubin P; miRagen Therapeutics, Inc, Boulder, Colorado, USA., Marshall WS; miRagen Therapeutics, Inc, Boulder, Colorado, USA.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2019 May; Vol. 139 (5), pp. 1073-1081. Date of Electronic Publication: 2018 Nov 22.
DOI:	10.1016/j.jid.2018.11.007
Abstrakt:	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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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