A synthetic microRNA‐92a inhibitor (MRG‐110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds

Abstract

There is a strong unmet need for new therapeutics to accelerate wound healing across both chronic and acute indications. It is well established that local tissue hypoxia, vascular insufficiency, and/or insufficient angiogenesis contribute to inadequate wound repair in the context of diabetic foot ulcers as well as to other chronic wounds such as venous stasis and pressure ulcers. microRNA-92a-3p (miR-92a) is a potent antiangiogenic miRNA whose inhibition has led to increases in angiogenesis in multiple organ systems, resulting in an improvement in function following myocardial infarction, limb ischemia, vascular injury, and bone fracture. Due to their pro-angiogenic effects, miR-92a inhibitors offer potential therapeutics to accelerate the healing process in cutaneous wounds as well. This study investigated the effect of a development stage locked nucleic acid-modified miR-92a inhibitor, MRG-110, in excisional wounds in db/db mice and in normal pigs. In both acute and chronic wounds, MRG-110 increased granulation tissue formation as assessed by histology, angiogenesis as assessed by immunohistochemistry and tissue perfusion, and wound healing as measured by time to closure and percent closure over time. The effects of MRG-110 were greater than those that were observed with the positive controls rhVEGF-165 and rhPDGF-BB, and MRG-110 was at least additive with rhPDGF-BB when co-administered in db/db mouse wounds. MRG-110 was found to up-regulate expression of the pro-angiogenic miR-92a target gene integrin alpha 5 in vitro in both human vascular endothelial cells and primary human skin fibroblasts and in vivo in mouse skin, demonstrating its on-target effects in vitro and in vivo. Additional safety endpoints were assessed in both the mouse and pig studies with no safety concerns noted. These studies suggest that MRG-110 has the potential to accelerate both chronic and acute wound healing and these data provide support for future clinical trials of MRG-110.

Mechanistic Actions of microRNAs in Diabetic Wound Healing

“…Moreover, the miR-19 component of this cluster negatively controls WNT-signaling and angiogenesis to produce a denser vascular tree [ 180 ]. Furthermore, potentiating the miR-92a inhibition as a therapeutic strategy for chronic wounds is in the developmental stages, the locked nucleic acid (LNA)-modified miR-92a inhibitor, MRG-110, was confirmed to increase the expression of pro-angiogenic miR-92a target gene Itga5 in vitro and in vivo ( Table 2 , Table 3 and Table 4 ) [ 183 ].…”

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.…”

The discovery and development of topical medicines for wound healing

“…In murine models, upregulation of miR-92a decreased angiogenesis while inhibition of miR-92a improved wound healing and angiogenesis [90]. Inhibition of miR-92a with the inhibitor MRG-110 has also demonstrated accelerated wound healing in healthy pigs and diabetic mice [90], and consequently there are ongoing clinical trials with this inhibitor in healthy volunteers (NCT03603431).…”