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

Corrie L. Gallant-Behm*, Joseph Piper, Joshua M. Lynch, Anita G. Seto, Seok Jong Hong, Thomas A. Mustoe, Catherine Maari, Linda A. Pestano, Christina M. Dalby, Aimee L. Jackson, Paul Rubin, William S. Marshall

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1073-1081
Number of pages9
JournalJournal of Investigative Dermatology
Volume139
Issue number5
DOIs
StatePublished - May 2019

Fingerprint

MicroRNAs
Biomarkers
Extracellular Matrix
Skin
Pharmacodynamics
Collagen
Healthy Volunteers
Fibrosis
Hypertrophic Cicatrix
Polymerase chain reaction
RNA-Directed DNA Polymerase
Keloid
Fibroblasts
Pulmonary Fibrosis
Cell culture
Controlled Clinical Trials
Wounds and Injuries
tebufenozide
Rats
Reverse Transcriptase Polymerase Chain Reaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

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. / A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin. In: Journal of Investigative Dermatology. 2019 ; Vol. 139, No. 5. pp. 1073-1081.
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abstract = "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.",
author = "Gallant-Behm, {Corrie L.} and Joseph Piper and Lynch, {Joshua M.} and Seto, {Anita G.} and Hong, {Seok Jong} and Mustoe, {Thomas A.} and Catherine Maari and Pestano, {Linda A.} and Dalby, {Christina M.} and Jackson, {Aimee L.} and Paul Rubin and Marshall, {William S.}",
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Gallant-Behm, CL, Piper, J, Lynch, JM, Seto, AG, Hong, SJ, Mustoe, TA, Maari, C, Pestano, LA, Dalby, CM, Jackson, AL, Rubin, P & Marshall, WS 2019, 'A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin', Journal of Investigative Dermatology, vol. 139, no. 5, pp. 1073-1081. https://doi.org/10.1016/j.jid.2018.11.007

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

In: Journal of Investigative Dermatology, Vol. 139, No. 5, 05.2019, p. 1073-1081.

Research output: Contribution to journalArticle

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T1 - A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin

AU - Gallant-Behm, Corrie L.

AU - Piper, Joseph

AU - Lynch, Joshua M.

AU - Seto, Anita G.

AU - Hong, Seok Jong

AU - Mustoe, Thomas A.

AU - Maari, Catherine

AU - Pestano, Linda A.

AU - Dalby, Christina M.

AU - Jackson, Aimee L.

AU - Rubin, Paul

AU - Marshall, William S.

PY - 2019/5

Y1 - 2019/5

N2 - 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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