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 language | English (US) |
|---|---|
| Pages (from-to) | 1073-1081 |
| Number of pages | 9 |
| Journal | Journal of Investigative Dermatology |
| Volume | 139 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2019 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Dermatology
- Cell Biology
Cite this
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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 journal › Article
TY - JOUR
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85059659042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059659042&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2018.11.007
DO - 10.1016/j.jid.2018.11.007
M3 - Article
C2 - 30472058
AN - SCOPUS:85059659042
VL - 139
SP - 1073
EP - 1081
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 5
ER -