Overview
When inappropriately expressed or mutated, microRNAs cause significant changes in critical biological pathways and, as such, represent potential targets whose selective modulation could alter the course of a disease. Indeed, pioneering studies by Regulus scientists and collaborators have demonstrated that modulating microRNAs can effectively regulate biological processes and produce therapeutically beneficial results.
Regulus is advancing microRNA therapeutics in several areas including hepatitis C infection, cardiovascular disease, fibrosis, oncology, immuno-inflammatory diseases, and metabolic diseases.
Hepatitis C
Regulus' lead program is for Hepatitis C Virus infection (HCV) focused on miR-122. Regulus scientists and collaborators performed pioneering studies to show that anti-miR-122 reduces cholesterol levels in blood and reverses hepatic steatosis (fatty liver) in obese mice. More recent pre-clinical studies show that miR-122 is essential for replication of HCV. Together, these findings suggest that anti-miR-122 may both reduce HCV infection and, in addition, improve HCV-associated pathologies like steatosis. We are therefore advancing anti-miR-122 to clinical studies for HCV.
Fibrosis
Regulus is also advancing a program for fibrotic diseases, targeting miR-21. Pre-clinical studies by Regulus and collaborators have shown that anti-miR-21 can reverse fibrosis and significantly improve cardiac function in mice with failing hearts. Regulus scientists and collaborators have shown more recently that similar therapeutic results are observed in other models of fibrosis. We currently are optimizing compounds for selection as clinical candidates for treatment of fibrotic diseases.
Oncology
Numerous studies have implicated dysregulation of microRNAs in cancer. Expression of specific microRNAs may increase or decrease in tumors relative to normal tissue. In some instances, over-expressed microRNAs may have pro-oncogenic functions (e.g., miR-21). The therapeutic approach for this type of microRNA would be to block or antagonize the over-expressed microRNAs using anti-miRs. microRNAs whose expression is under-expressed or lost in tumors may sometimes have a tumor suppressor function. For instance, miR-34, which positively regulates the TP53 pathway, is lost in melanomas and neuroblastomas. The therapeutic approach for microRNAs whose expression is lost in tumors is to increase (mimic) or agonize their expression. Regulus scientists and collaborators are pursuing the use of anti-miRs (anti-miR-21) and miR mimics (miR-34) for treatment of liver cancers.
Immunology and Inflammation
In April 2008, Regulus and GlaxoSmithKline (GSK) announced an alliance that focuses on microRNA therapeutic development for immuno-inflammatory diseases. GSK and Regulus work closely together, with Regulus responsible for the discovery and development through to completion of clinical proof of concept, at which point GSK will have an exclusive option to license each compound for further development and commercialization on a worldwide basis. Regulus retains the right to further develop and commercialize compounds for which GSK does not exercise its option. The overall objective of this program is to identify microRNA-based therapeutics for immunology and inflammation. Especially critical is knowledge of the in vivo pharmacology of anti-miRs in cells of the immune system. We are developing methods to effectively deliver oligonucleotide drugs to cells of the immune system, as this is critical for successful outcome. We are also testing anti-miRs in selected immune/inflammation disease models. Our studies have demonstrated several potential therapeutically useful phenotypes accompanying in vivo anti-miR modulation of microRNA targets in immune cells.
Exploratory Programs
In addition to these drug discovery efforts, Regulus is addressing fundamental scientific questions regarding microRNAs and oligonucleotides. We seek to further develop our platform technology and to better understand the consequences of modulating microRNA function in tissues. We continue to develop novel chemistries to identify microRNAs inducing new phenotypes. Finally, we seek to leverage our extensive collaboration network to discover potential therapeutic applications for microRNAs. These encompass a number of potential therapeutic areas, but focus most heavily on tissues most accessible to oligonucleotide drugs (liver, kidney, macrophages, etc). Most recently, exploratory studies have demonstrated glucose lowering and improvement in insulin sensitivity of obese mice following anti-miR modulation of microRNA targets in liver and/or adipose tissue.
