A novel angiogenic microRNA drug might be a new option for the treatment of ischemic cardiovascular disease, according to a new study (“Nuclear microRNA-466c regulates Vegfa expression in response to hypoxia”) in PLOS ONE by researchers from the University of Eastern Finland together with international collaborators. In the study, the researchers describe a novel nuclear acting microRNA.
MicroRNAs are small RNA molecules, which regulate gene expression. Their recognized role is gene silencing by targeting messenger RNAs in cell cytoplasm. However, this novel microRNA, miR-466c, has a different mechanism of action. It upregulates the vascular endothelial growth factor A (VEGFA) by targeting the gene promoter in the cell nucleus.
In addition to expanding the academic understanding of microRNA biology, these findings have commercial relevance for the development of novel RNA drugs. Increasing the expression of VEGFA by using small RNAs offers novel options for the treatment of ischemic cardiovascular disease, where the blood supply in the tissue is compromised.
“MicroRNAs are well characterized in their role in silencing gene expression by targeting 3´—UTR of mRNAs in cytoplasm. However, recent studies have shown that miRNAs have a role in the regulation of genes in the nucleus, where they are abundantly located,” write the investigators.
“We show here that in mouse endothelial cell line (C166), nuclear microRNA miR-466c participates in the regulation of vascular endothelial growth factor a (Vegfa) gene expression in hypoxia. Upregulation of Vegfa expression in response to hypoxia was significantly compromised after removal of miR-466c with CRISPR-Cas9 genomic deletion. We identified a promoter-associated long non-coding RNA on mouse Vegfa promoter and show that miR-466c directly binds to this transcript to modulate Vegfa expression.
“Collectively, these observations suggest that miR-466c regulates Vegfa gene transcription in the nucleus by targeting the promoter and expands on our understanding of the role of miRNAs well beyond their canonical role.”
“RNA activation as a phenomenon has been known for 16 years already, but its commercial potential has been recognized only recently,” says Adjunct Professor Mikko Turunen, PhD, adjunct professor at the University of Eastern Finland, and chair of the newly founded RNatives company, which will be commercializing the patented microRNA drug.
“Our patented microRNA drug has several advantages over traditional means of increasing gene expression. First of all, by activating the cell’s own therapeutic gene (e.g., VEGFA), all the different spliceforms of the gene are correctly produced. Also, being a small RNA, it is much less immunogenic and more stable than longer RNAs, such as mRNA based drugs,” continues Turunen.
In addition to RNA drugs, RNatives is developing engineered exosomes for the delivery of these RNAs into patients.