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Wednesday, May 11, 2011


Regulus Therapeutics and Collaborators Present New Results from Preclinical Research on microRNA Therapeutics in Metabolic Disease

Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative new medicines targeting microRNAs, today announced the presentation of new preclinical data from its cardiovascular and metabolic disease program, performed in collaboration with scientists at New York University (NYU) and Wake Forest University. The data were presented at the American Heart Association’s Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2011 Scientific Sessions held April 28-30, 2011 in Chicago, Ill. In an oral presentation titled “microRNA Regulation of Cholesterol Homeostasis,” proprietary chemically modified therapeutic anti-miRs targeting microRNA-33a (miR-33a) and microRNA-33b (miR-33b) were shown to increase levels of high density lipoprotein cholesterol (HDL-C), or ‘good’ cholesterol, and reduce levels of blood triglycerides in non-human primates.

“This important study is the first-ever demonstration of therapeutic benefits resulting from the modulation of a microRNA and its downstream pathways in non-human primates. Equally important, the data support the development of anti-miR-33 as a potential new therapeutic for dyslipidemia, atherosclerosis, and other related metabolic diseases by showing significant increases in levels of HDL-C and lowering of triglycerides,” said Hubert Chen, M.D., vice president of translational medicine of Regulus. “Regulus is advancing several microRNA therapeutic programs to the clinic, including anti-miR-33.”

The new in vivo research was performed using an experimental design of feeding non-human primates a high carbohydrate, moderate cholesterol diet. anti-miR-33 was administered subcutaneously at a dose of 5 mg/kg twice weekly for the first two weeks and then once weekly for the remainder of the 12 week study. Plasma lipids were analyzed weekly, and non-human primates treated with anti-miR-33 compared to mismatch control showed a 50% increase in HDL-C and a 50% decrease in blood triglycerides. Further, anti-miR-33 treatment increased the expression of miR-33a and miR-33b target genes involved in clearance of excess cholesterol from cells to the liver for excretion to the bile and feces, known as reverse cholesterol transport, and also genes involved in fatty acid oxidation that could be responsible for the observed triglyceride lowering.

Kathryn Moore, Ph.D., associate professor in the Department of Medicine at NYU Langone Medical Center and presenting author said, “Much progress has been made in understanding the molecular mechanisms that regulate cholesterol and fatty acid metabolism and the role of microRNAs in this complex genetic network. Our studies with Regulus show that miR-33 specifically targets genes involved in HDL-C biogenesis, cholesterol efflux and fatty acid oxidation, and its antagonism results in direct upregulation of these pathways with clear potential for therapeutic benefit. Modulating dysregulated microRNAs with therapeutic anti-miRs holds tremendous promise as a new innovative class of medicines.”

“Coronary artery disease remains a major killer in the developed world pointing to the need for novel therapeutic approaches,” said Ryan Temel, Ph.D., assistant professor at Wake Forest School of Medicine. “This study in non-human primates demonstrates that anti-miR-33 might be a promising clinical approach in the treatment of cardiovascular disease.”

Regulus is developing microRNA therapeutics targeting both miR-33a and miR-33b. Regulus controls fundamental patent rights related to miR-33, including the miR-33 sequence and complementary sequences covered in the Tuschl III patent series. Additional Regulus patent rights include compositions of matter for various chemically modified anti-miR-33 compounds and methods of use for the treatment of metabolic diseases with anti-miR-33.

About miR-33

Cholesterol metabolism is tightly regulated at the cellular level and recent discoveries have shown that microRNA-33 (miR-33) modulates genes involved in cellular cholesterol transport. miR-33a and miR-33b are found in the introns of the SREBP-2 and SREBP-1 genes, transcriptional regulators of cholesterol and fatty acid synthesis, respectively. Inhibition of miR-33a and miR-33b increases cholesterol efflux in the liver and peripheral macrophages through upregulation of the target gene ABCA1. As a result, HDL cholesterol levels increase and reverse cholesterol transport is enhanced, making miR-33 a promising target for treatment of atherosclerosis. Additional targets of miR-33a and miR-33b in the fatty acid oxidation and insulin signaling pathways have also suggested that miR-33a and miR-33b inhibition will be beneficial for multiple aspects of metabolic syndrome.

About microRNAs

The discovery of microRNA in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 700 microRNAs have been identified in the human genome, and over one-third of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNAs have been shown to play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Most microRNAs are conserved across multiple species, indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression, or function, has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections. Targeting microRNAs with anti-miRs, antisense oligonucleotide inhibitors of microRNAs, or miR-mimics, double-stranded oligonucleotides to replace microRNA function opens potential for a novel class of therapeutics and offers a unique approach to treating disease by modulating entire biological pathways.

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