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 several distinct programs, both independently and with our strategic alliance partners, AstraZeneca and Sanofi.
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.
Hepatitis C is a result of a hepatocyte specific infection induced by the virus known as HCV. Chronic HCV may lead to significant liver disease, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Up to 170 million people are chronically infected with HCV worldwide, and more than 350,000 people die from HCV annually. The CDC estimates that there are currently approximately 3.2 million persons infected with HCV in the United States. HCV shows significant genetic variation in worldwide populations due to its frequent rates of mutation and rapid evolution. There are six genotypes of HCV, with several subtypes within each genotype, which vary in prevalence across the different regions of the world. The response to treatment varies from individual to individual underscoring the inadequacy of existing therapies and highlights the need for combination therapies that not only target the virus but endogenous host factors as well, such as microRNA-122.
Regulus believes that its’ miR-122 antagonist, RG-101, a wholly-owned, GalNac-conjugated anti-miR targeting microRNA-122 for the treatment of HCV, may be a useful agent in emerging combination regimens to address difficult-to-treat genotypes and to potentially expand upon the current therapies available to clinicians treating HCV patients.
We have identified microRNA signatures in several different models of fibrotic disease. These data suggest that microRNAs drive the pathogenesis of fibrotic disease.
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.
Many if not all cancers display abnormal expression of microRNAs. This dysregulation has been shown to promote tumor progression and metastasis. Treating cancers with microRNA therapeutics offers a promising new approach to many different cancers.
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). miR-21 is one of the most validated microRNA targets in oncology, with numerous scientific publications suggesting that miR-21 plays an important role in the initiation and progression of cancers including liver, kidney, breast, prostate, lung and brain. Similarly, miR-221 has been identified to be upregulated in multiple cancers including liver, kidney, prostate, brain, thyroid, ovarian, and breast cancer. In addition there is genetic evidence that links miR-21 and miR-221 to Hepatocellular carcimona, or HCC.
HCC, is the most prevalent form of liver cancer and is the most common cancer in some parts of the world, with more than 1 million new cases diagnosed each year worldwide according to the National Cancer Institute. According to the World Health Organization, liver cancer is the third leading cause of cancer deaths worldwide. According to recent reports from the Centers for Disease Control, or the CDC, HCC rates in the United States are increasing with common risk factors including alcohol consumption, metabolic syndrome and type 2 diabetes.
Regulus is developing oncology anti-miRs targeting miR-21 and miR-221, which we refer to as anti-miR-21 and anti-miR-221, for HCC because our analysis of liver biopsies from HCC patients has shown that miR-21 and miR-221 are up-regulated relative to surrounding normal liver tissues. Regulus has also shown that miR-21 and miR-221 levels are increased in a genetically engineered mouse that develops HCC, thereby enabling us to test anti-miR-21 and anti-miR-221 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.
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.
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.