Fibrosis
“We have identified microRNA signatures in several different models of fibrotic disease. These data suggest that microRNAs drive the pathogenesis of fibrotic disease.”
~ Deidre MacKenna, Ph.D.
Director of Pharmacology
Fibrosis is the harmful build-up of excessive fibrous tissue leading to scarring and ultimately the loss of organ function. Fibrosis can affect any tissue and organ system, and is most common in the heart, liver, lung, peritoneum, and kidney. The fibrotic scar tissue is made up of extracellular matrix proteins such as type I collagen, proteoglycans and fibronectin. Regulus has identified several microRNAs that are dysregulated in fibrosis.
Regulus’ lead program for fibrosis targets microRNA-21 (miR-21), which is upregulated in fibrotic tissues of humans. Pre-clinical studies by Regulus scientists and collaborators have shown that anti-miR-21 can impact fibrosis in preclinical models by reducing expression of extracellular matrix proteins, as well as significantly improve organ function in multiple models of fibrosis including heart and kidney.
Regulus plans to identify an anti-miR-21 development candidate to advance into clinical studies for the treatment of fibrotic diseases.
See below for select publications on microRNAs in fibrosis
Thum T., J Clin Invest 2010. Comparison of different miR-21 inhibitor chemistries in a cardiac disease model. http://www.ncbi.nlm.nih.gov/pubmed/21285516
Thum T., Nature 2008. microRNA-21 contributes to myocardial disease by stimulating MAP kinase signaling in fibrosis.http://www.ncbi.nlm.nih.gov/pubmed/19043405
Hepatitis C Virus
“miR-122 is a liver-expressed microRNA that has been shown to be a critical endogenous “host factor” for the replication of HCV, and anti-miRs targeting miR-122 have been shown to block HCV infection.”
~ Hubert C. Chen, M.D.
Vice President of Translational Medicine
Hepatitis C Virus (HCV) is a major cause of acute hepatitis and chronic liver diseases such as cirrhosis and liver cancer. Globally, an estimated 170 million people – three percent of the world’s population – are chronically infected with HCV and three to four million more become infected each year.
Regulus’ lead program for HCV is focused on microRNA-122 (miR-122). Recent pre-clinical studies have shown that miR-122 is essential for replication of HCV. These findings suggest that anti-miR-122 might reduce HCV infection. Regulus plans to identify an anti-miR-122 development candidate to advance into clinical studies for the treatment of HCV infection.
See below for select publications on microRNAs in HCV.
Immuno-inflammatory
“Recent studies have shown that microRNAs have unique expression profiles in cells of the innate and adaptive immune systems and when dysregulated they can contribute to pathological conditions ofthe immune system.”
~ James Karras, Ph.D.
Senior Director of Immunology
Immune-mediated diseases are conditions that result from abnormal activity of the body’s immune system. One component of the immune response is the inflammatory process. Inflammation is part of the complex biological response of vascular tissues and immune cells to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the body to remove the injurious stimuli and to initiate the healing process. However, misguided inflammatory responses are a main driver in a host of diseases ranging from allergies to atherosclerosis. Ultimately, progressive destruction of the tissue through the inflammatory process can compromise the survival of the individual.
Regulus and collaborators have identified several microRNAs that play roles in the immune system and inflammatory processes. Regulus’ lead program in the area of inflammatory diseases targets microRNA-155 (miR-155). Upon activation, miR-155 is expressed in several types of human immune cells, including B cells, T cells, macrophages and dendritic cells. Targeting miR-155 with anti-miRs may offer a novel therapeutic approach for treating inflammatory diseases.
See below for select publications on microRNAs in inflammation.
Metabolic
“microRNAs have been shown to be key regulators of glucose and lipid metabolism. The modulation of specific microRNAs is a promising strategy to treat metabolic disease.”
~ Christy Esau Ph.D.
Associate Director of Metabolic Diseases
Metabolic diseases are a worldwide, growing health problem, and there is a grave need for safe and effective therapies. MicroRNAs have been implicated in the dysregulation of glucose and lipid metabolism leading to metabolic and cardiovascular disorders such as type 2 diabetes and atherosclerosis. Using preclinical models of metabolic disease and disease tissues from patients, Regulus has identified several microRNAs with therapeutic potential in this area.
Regulus’ lead program for metabolic disease targets microRNA-33a (miR-33a) and microRNA-33b (miR-33b). miR-33a and -b are found in the introns of SREBF2 and SREBF1 transcription factors, respectively, and work in concert with their host genes to regulate cholesterol and fatty acid synthesis. miR-33a/b target the cellular cholesterol efflux transporter ABCA1, as well as key regulators of fatty acid oxidation and insulin signaling, suggesting that inhibition of miR-33 could have therapeutic benefit in atherosclerosis and other aspects of the metabolic syndrome, including hepatosteatosis and insulin resistance. Studies in mice showed that antagonizing miR-33a enhanced reverse cholesterol transport, promoted regression of atherosclerosis by increasing ABCA1 in the liver and peripheral macrophages, and raised plasma HDL cholesterol (Rayner et.al., J. Clin. Invest., 2011). We have now translated these findings to non-human primates, demonstrating in African green monkeys that systemic delivery of an anti-miR-33a/b increased hepatic expression of ABCA1 and induced a sustained increase in circulating HDL cholesterol (Rayner et. al., Nature, 2011). In addition, there was a ~50% decrease in plasma triglycerides. These results show that targeting miR-33a/b is a promising therapeutic strategy for atherosclerosis and other aspects of the metabolic syndrome.
See below for select publications on microRNAs in metabolic disease.
▪ Rayner K., Nature 2011. Inhibition of miR-33a/b in non-human primates raises plasma HDL and loweres VLDL triglycerides. http://www.ncbi.nlm.nih.gov/pubmed/22012398
▪ Rayner K., J Clin Invest 2011. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. http://www.ncbi.nlm.nih.gov/pubmed/21646721
▪ Trajkovski, M., Nature 2011. microRNAs 103 and 107 regulate insulin sensitivity. http://www.ncbi.nlm.nih.gov/pubmed/21654750
Oncology
“Many if not all cancers display abnormal expression of microRNAs. This dysregulation has been shown to promote tumor progression & metastasis. Treating cancers with microRNA therapeutics offers a promising new approach to many different cancers.”
~ Eric Marcusson Ph.D.
Senior Director Oncology
Genome-wide expression studies have demonstrated that almost all cancer types present altered microRNAs that are either upregulated or downregulated. Growing evidence has demonstrated that microRNAs can act as either oncogenes or tumor suppressor genes, and mutations or aberrant expression can promote tumorigenesis. Regulus has identified several dysregulated microRNAs in preclinical cancer models as well as in cells/tissues from cancer patients.
Regulus’ lead program in oncology targets microRNA-21 (miR-21). Recent studies have demonstrated that miR-21 is overexpressed in many cancer types (Volinia et al., PNAS. 2006) and can promote tumor progression and metastasis (Medina et al., Nature. 2010). Regulus data has shown that miR-21 is upregulated in patients with hepatocellular carcinoma (HCC). In preclinical models of HCC, short-term treatment (2-3 weeks) with anti-miR-21 inhibited miR-21 in the liver and reduced liver tumor formation. Longer-term treatment (17 weeks) with anti-miR-21 resulted in a significant survival advantage (p<0.0001) over saline and control anti-miR treated mice. These findings suggest that miR-21 is a promising target for cancer.
In addition to our lead program miR-21, Regulus is working on several other microRNAs that appear to be involved in several different types of cancer.
See below for select publications on microRNAs in cancer.
Exploratory
In addition to the select drug discovery and development programs highlighted above, Regulus has a significant internal exploratory effort focused on new target identification and assay development. In addition to internal discovery efforts, Regulus also leverages its extensive network of leading academic collaborators to discover new microRNAs and support microRNA discovery efforts that feed the Company’s pipeline.
See below for select publications from these exploratory efforts.
