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

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-ofmechanism; 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.

Unveiling ncRNA regulatory axes in atherosclerosis progression

“…Thus, the first siRNA‐based drug (Patisiran) has recently obtained the FDA approval to silence the transthyretin (TTR) mRNA (via RNA‐interference by binding its 3′UTR) which caused a rare transthyretin‐mediated amyloidosis polyneuropathy originated by the deposit of TTR‐protein in tissues [121]. Other miRNA‐candidates for medical intervention are currently in clinical development or in phase 1 or phase 2 clinical trials, such as MRG‐110, a locked nucleic acid (LNA)‐modified antisense oligonucleotide against miR‐92 with a potential clinical application in wound healing and heart failure [122], a miR‐29b mimic (Remlarsen) to prevent formation of fibrotic scars or cutaneous fibrosis [123], or anti‐miR‐21 oligonucleotides, which were seen to alleviate kidney disease in a murine model of Alport nephropathy [124]. On the other hand, miRNA‐mimics or antagomirs have been also used at the laboratory level to modulate miRNA expression in ATH research [125], and recently therapies directed against miR‐449a [126], miR‐23a‐5p [109], or miRNA‐98 [112], among others, have been tried in animal models with encouraging results.…”

Improved tendon healing by a combination of Tanshinone IIA and miR-29b inhibitor treatment through preventing tendon adhesion and enhancing tendon strength

“…Many studies have shown that microRNA is emerging as vital homeostatic regulators of tissue repair (16). The miRNA-29 (miR-29) plays an important role in the regulation of key process of fibrosis and scar formation (17). In our previous study, we also found that TSA treatment enhanced the expression level of miR-29b (12).…”

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

“…A significant reduction in the leukemic progression and increase survival of the study cohort was recorded indicating that miR-181b could potentially be used to reduce the expansion of CLL B-cells in patients [217]. In addition, miR-29 [218] and miR-125a [219] inhibitors and miRNA mimics are also under investigation for the treatment of different diseases (www.miRagen.com). However, the regulation of miR-29 and miR-125 expression in CLL is extremely complex end thus no study has yet evaluated these microRNA as a therapeutic agent for CLL treatment.…”