Fibrosis is a harmful build-up of excessive fibrous tissue that results in scarring, and ultimately, the loss of organ function. Although it can affect any tissue and organ system, it is most common in the heart, liver, lung, peritoneum, and kidney. The fibrotic scar tissue consists of extra-cellular matrix proteins, such as type I collagen, proteoglycans and fibronectin.

Regulus, a biopharmaceutical leader in the discovery and development of innovative medications that targets microRNAs, has discovered a number of microRNAs that impair the physiological regulatory mechanism in fibrosis, and has announced their new preclinical study results in the Science Translational Medicine journal, demonstrating that miR-21 contributed to fibrogenesis, and that it can be a suitable candidate as a target for anti-fibrotic therapies.

MicroRNA in humans are small RNA molecules that are typically 20 to 25 nucleotides in length, which do not encode proteins, but regulate gene expression. Discovered in the last decade, they represent one of the most exciting scientific breakthroughs in recent history. Researchers have discovered over 700 microRNAs in the human genome, with more than a third of all human genes thought to be regulated by microRNAs.

Given that a single microRNA is able to regulate entire networks of genes, these molecules are considered master regulators of the human genome. microRNAs have demonstrated their integral role in several biological processes, such as in immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development.

Most microRNAs are conserved across multiple species, which suggests that these molecules have an evolutionary importance as modulators of critical biological pathways. microRNA expression or function, has demonstrated to substantially alter in many states if diseases, such as cancer, heart failure and viral infections.

By targeting microRNAs with anti-miRs, antisense oligonucleotide inhibitors of microRNAs, or miR-mimics, double-stranded oligonucleotides to replace microRNA function, research has discovered a new potential for a novel class of therapeutics that provide a unique approach for the treatment of diseases by modulating entire biological pathways.

Neil W. Gibson, Ph.D., Regulus’ Chief Scientific Officer announced:

“We are pleased with the published results demonstrating that targeting miR-21 with proprietary anti-miR oligonucleotides is effective at preventing kidney fibrosis in preclinical models. We plan to select an anti-miR-21 development candidate this year for advancement into the clinic in the near future and are excited about the potential to bring this innovative treatment to patients with fibrotic diseases.”

Dr. Duffield, M.D., Ph.D. Associate Professor of Medicine, in the Division of Nephrology, at the University of Washington explained:

“Expression of miR-21 was found to be increased in fibrotic kidney samples from animal models and human patient samples. Genetic deletion of miR-21 in preclinical models protected kidneys from fibrosis and treatment with anti-miRs targeting miR-21 also blocked fibrosis in preclinical models. Taken together, these data suggest that anti-miR-21 could have a therapeutic benefit in patients with chronic kidney disease.”

The study focused on fibrosis targets miR-21 that increase cells in fibrotic tissues of humans. According to Regulus’ earlier preclinical research, therapeutic oligonucleotides targeting miR-21 (anti-miR-21) has the ability to lower fibrosis in preclinical models through reducing the expression of extracellular matrix proteins. Even though many people are currently affected by fibrosis-related disease, few therapies are available to specifically treat this devastating illness.

Regulus and collaborators from the University of Washington examined the effect of miR-21 in kidney fibrosis, and even though they discovered no overt abnormality when genetically deleting miR-21 in mice, they did observe that these miR-21 knock out mice experienced less fibrosis in response to kidney injury, which was pheno-copied in wild-type mice treated with anti-miR-21 oligonucleotides.

The researchers analyzed gene expression profiles and detected groups of genes, especially those involved in lipid metabolism and enhanced oxygen radical production, that were involved in metabolic pathways that were up-regulated in the absence of miR-21. They observed that by systematically administering anti-miR-21, the harmful effects of miR-21 in kidney injuries were successfully reversed.

The results of the two mouse model studies prove that miR-21 contributes to fibrogenesis and epithelial injury in the kidneys. Furthermore, the findings support that miR-21 is a suitable candidate target for anti-fibrotic therapies.

Written by Petra Rattue