Regulus is developing single-stranded oligonucleotides, which are chemically synthesized chains of nucleotides that are mirror images of specific target microRNAs. We incorporate proprietary chemical modifications to enhance drug properties such as potency, stability and tissue distribution. We refer to these chemically modified oligonucleotides as anti-miRs. Each anti-miR is designed to bind with and inhibit a specific microRNA target that is up-regulated in a cell and that is involved in the disease state. In binding to the microRNA, anti-miRs correct the dysregulation and return diseased cells to their healthy state. We have demonstrated therapeutic benefits of our anti-miRs in at least 20 different preclinical models of human diseases. Regulus is currently optimizing anti-miRs in five distinct programs, both independently and with our strategic alliance partners, AstraZeneca, GlaxoSmithKline and Sanofi.
“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.
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.”
~ Bal Bhat, Ph.D.
Senior Director, Medicinal Chemistry
Hepatitis C Virus (HCV) is a major cause of acute hepatitis and chronic liver diseases such as cirrhosis and liver cancer. According to the World Health Organization, up to 170 million people are chronically infected with HCV and three to four million more become infected each year.
Regulus has nominated its first microRNA candidate for clinical development, RG-101, a GalNAc-conjugated microRNA antagonist or anti-miR, which targets microRNA-122 (miR-122) for the treatment of patients with chronic hepatitis C virus (HCV) infection. Regulus is performing additional pre-clinical studies and finalizing development plans for RG-101 in HCV and expects to submit an application with regulatory authorities in early 2014.
“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
Atherosclerosis is the build-up of plaque that occurs when cholesterol and inflammatory cells accumulate in blood vessels. These plaques can rupture, leading to slowing or blockage of blood flow and ultimately resulting in a heart attack or stroke. Scientific research has shown a strong correlation between high cholesterol levels and cardiovascular disease which, according to the Centers for Disease Control, is the leading cause of death in the United States.
Regulus’ lead program for atherosclerosis targets microRNA-33, which has a unique mechanism of action for the management of cholesterol levels. The inhibition of microRNA-33 with our anti-miRs promotes reverse cholesterol transport, or RCT, which is the efflux of cholesterol from specific cholesterol-laden inflammatory cells called macrophages in atherosclerotic plaques. Treatment with anti-microRNA-33 in an atherosclerotic mouse model led to reduction in arterial plaque size by 35% (Rayner et al., J Clin Invest. 2011) and treatment in non-human primates increased circulating levels of HDL-C by 50%. By enhancing RCT, anti-miR-33 differs from other emerging therapeutic strategies that focus only on raising HDL-C in circulation.
“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.”
~ Sonya Zabludoff, 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). Numerous scientific publications suggest that miR-21 plays an important role in the initiation and progression of cancers including liver, kidney, breast, prostate, lung and brain. Regulus is developing oncology anti-miRs targeting miR-21, which we refer to as anti-miR-21, for hepatocellular carcinoma (HCC) because our analysis of liver biopsies from HCC patients has shown that miR-21 is up-regulated approximately three-fold in tumors relative to surrounding normal liver tissues. We have also shown that miR-21 levels are increased approximately three-fold in a genetically engineered mouse that develops HCC, thereby enabling us to test anti-miR-21 in a preclinical model that mimics the human disease. Testing anti-miR-21 in this mouse model of HCC showed delayed tumor progression resulting in a survival rate of 80% at the study endpoint (compared to a 0% survival rate for the control group).
GBM, also known as glioblastoma or grade IV astrocytoma, is an aggressive tumor that forms from abnormal growth of glial (supportive) tissue of the brain. According to the New England Journal ofMedicine, GBM is the most prevalent form of primary brain tumor and accounts for approximately 50% of the 22,500 new cases of brain cancer diagnosed in the United States each year. Treatment options are limited and expected survival is little over one year. GBM is considered a rare, or orphan, disease by the FDA and EMA.
Our findings show that treatment of GBM cell lines with anti-miRs targeting miR-10b reduces proliferation by blocking cell cycle progression and triggering cell death. We have shown in preclinical animal models of GBM that direct injection into the tumor and spinal fluid achieves appropriate tissue delivery of anti-miRs for potential therapeutic effects. We have a research collaboration with the Samsung Biomedical Research Institute to assist us in testing our anti-miR-10b development candidates in specialized preclinical models that mimic human brain cancer. In addition, we have funding support from Accelerate Brain Cancer Cure, or ABC2, a non-profit organization dedicated to accelerating therapies for brain cancer patients.
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.