-Regulus, in partnership with Sanofi, developing novel anti-fibrotic therapies targeting microRNAs 

LA JOLLA, Calif., Feb. 16, 2012 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that new preclinical data investigating the role of microRNA-21 (miR-21) in the treatment of kidney fibrosis has been published in the journal Science Translational Medicine. Regulus’ lead program for fibrosis targets miR-21, which is up-regulated in fibrotic tissues of humans. Previous preclinical studies by Regulus scientists and collaborators have shown that therapeutic oligonucleotides targeting miR-21 (anti-miR-21) can decrease fibrosis in preclinical models by reducing the expression of extracellular matrix proteins.  Despite the current burden of fibrosis-related human disease, there are few therapies that can specifically treat this devastating disease.

“We are pleased with the published results demonstrating that targeting miR-21 with proprietary anti-miR oligonucleotides is effective at preventing kidney fibrosis in preclinical models,” said Neil W. Gibson, Ph.D., Regulus’ Chief Scientific Officer.  “We plan to select an anti-miR-21 development candidate this year for advancement into the clinic in the near future and are excited about the potential to bring this innovative treatment to patients with fibrotic diseases.”

 “Expression of miR-21 was found to be increased in fibrotic kidney samples from animal models and human patient samples. Genetic deletion of miR-21 in preclinical models protected kidneys from fibrosis and treatment with anti-miRs targeting miR-21 also blocked fibrosis in preclinical models,” said Dr. Duffield, M.D., Ph.D. Associate Professor of Medicine, in the Division of Nephrology, at the University of Washington. “Taken together, these data suggest that anti-miR-21 could have a therapeutic benefit in patients with chronic kidney disease.”

In the published study, Regulus and its collaborators from the University of Washington investigated the role of miR-21 in kidney fibrosis. Genetic deletion of miR-21 in mice resulted in no overt abnormality, however, these miR-21 knock out mice suffered less fibrosis in response to kidney injury, which was pheno-copied in wild-type mice treated with anti-miR-21 oligonucleotides. Analysis of gene expression profiles identified groups of genes involved in metabolic pathways that were up-regulated in the absence of miR-21, in particular genes involved in lipid metabolism and enhanced oxygen radical production.  Systemic administration of anti-miR-21 effectively reversed the deleterious effects of miR-21 in kidney injuries.  These animal studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for anti-fibrotic therapies. 

The journal article titled, “MicroRNA 21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways,” is now available in Science Translational Medicine and on the publications page of the Regulus website at www.regulusrx.com.   

 About Fibrosis

 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.  Results from this new preclinical study demonstrate that miR-21 contributed to fibrogenesis and is a candidate target for anti-fibrotic therapies. 

 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. 

 About Regulus Therapeutics, Inc.

 Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

 For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx.

Forward-Looking Statements 

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting microRNA -21 for treating fibrosis and kidney injury. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

Scarring of the kidney is a major public health concern, directly promoting loss of kidney function. To understand the role of microRNA (miRNA) in the progression of kidney scarring in response to injury, we investigated changes in miRNA expression in two kidney fibrosis models and identified 24 commonly up-regulated miRNAs. Among them, miR-21 was highly elevated in both animal models and in human transplanted kidneys with nephropathy. Deletion of miR-21 in mice resulted in no overt abnormality. However, miR-21^−/− mice suffered far less interstitial fibrosis in response to kidney injury, a phenotype duplicated in wild-type mice treated with anti–miR-21 oligonucleotides. Global derepression of miR-21 target mRNAs was readily detectable in miR-21^−/− kidneys after injury. Analysis of gene expression profiles up-regulated in the absence of miR-21 identified groups of genes involved in metabolic pathways, including the lipid metabolism pathway regulated by peroxisome proliferator–activated receptor-α (Pparα), a direct miR-21 target. Overexpression of Pparα prevented ureteral obstruction–induced injury and fibrosis. Pparα deficiency abrogated the antifibrotic effect of anti–miR-21 oligonucleotides. miR-21 also regulated the redox metabolic pathway. The mitochondrial inhibitor of reactive oxygen species generation Mpv17l was repressed by miR-21, correlating closely with enhanced oxidative kidney damage. These studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for antifibrotic therapies.

LA JOLLA, Calif., Jan. 5, 2012 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that data from its proprietary lead program targeting microRNA-33a/b  (miR-33a/b), currently in preclinical development for the treatment of atherosclerosis, will be presented at the Keystone Symposium “Nucleic Acid Therapeutics: From Base Pairs to Bedsides” held Jan. 10–15, 2012, in Santa Fe, New Mexico. In addition, information from its preclinical oncology programs will be presented at the American Association for Cancer Research’s (AACR) Noncoding RNAs and Cancer workshop held Jan. 8-11, 2012, in Miami, Florida.

 “We are pleased to present data about our proprietary microRNA programs in metabolic disease and oncology at the Keystone Symposium and AACR Special Conference respectively,” said Neil W. Gibson, Ph.D., Chief Scientific Officer of Regulus Therapeutics. “Our scientists have made significant progress discovering potent and safe therapeutic oligonucleotide anti-miRs. We look forward to selecting clinical candidates this year for the advancement of multiple microRNA therapeutic programs into the clinic.” 

• Keystone Symposium: A Regulus scientist will present that targeting miR-33a/b is a promising therapeutic strategy for atherosclerosis and other aspects of the metabolic syndrome in an oral presentation titled “Targeting miR-33 for Atherosclerosis” at 8 a.m. MST on January 14. miR-33a and miR-33b 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-33a/b 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.  Importantly, these findings have now been translated to non-human primates, demonstrating that systemic delivery of an anti-miR-33a/b oligonucleotide increased hepatic expression of ABCA1, induced a sustained increase in circulating HDL cholesterol and decreased plasma triglycerides.  
• AACR Special Conference: A Regulus scientist will present data demonstrating that microRNAs are dysregulated in cancer and are drivers of disease pathogenesis in an oral presentation titled “Anti-miR Therapeutics for Cancer” at 10:15 a.m. EST on January 11. Regulus’ oncology programs include targeting microRNA-21 (miR-21), which has been shown to be overexpressed in many cancer types promoting tumor progression and metastasis.  Regulus data has demonstrated that miR-21 is up-regulated in patients with hepatocellular carcinoma (HCC) and, in preclinical models of HCC, treatment with anti-miR-21 reduces tumor formation resulting in significant survival benefit. Other efforts in oncology include the discovery of microRNA therapeutics for the treatment of glioblastoma multiforme (GBM), an orphan and rare disease with limited treatment options, performed in collaboration with Samsung Medical Center and ABC², a non-profit organization dedicated to accelerating therapies for brain cancer patients.

 Regulus is advancing multiple microRNA therapeutic programs to the clinic in the areas of fibrosis, HCV infection, immuno-inflammatory disease, metabolic disease, and oncology.

 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. 

 About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx. 

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting microRNAs for metabolic disease and oncology. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

LA JOLLA, Calif., Dec. 12, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced the initiation of a new discovery effort in microRNA therapeutics for the treatment of glioblastoma multiforme (GBM), the most common and aggressive brain tumor in humans. Regulus will apply its expertise in microRNA therapeutics to discover chemically modified oligonucleotide anti-miRs for testing at the Samsung Medical Center in preclinical models that mimic human brain cancer. Accelerate Brain Cancer Cure (ABC²), a non-profit organization dedicated to accelerating therapies for brain cancer patients, has awarded Regulus a grant to support the research.

 “GBM is a devastating disease with limited treatment options,” said Neil W. Gibson, Ph.D. Chief Scientific Officer of Regulus Therapeutics. “At Regulus, we have successfully targeted microRNAs in multiple disease settings and believe that targeting dysregulated microRNAs using chemically modified oligonucleotide anti-miRs provides a potential therapeutic approach for GBM.”

 “A major hurdle in the discovery and development of novel therapeutics for GBM has been the lack of relevant animal models,” said Do Hyun Nam, Ph.D. Professor and Director of Institute for Refractory Cancer Research, Samsung Medical Center. “In our collaboration with Regulus, we will utilize a recently developed model in which tumors derived from human patients are transplanted into mice resulting in a model directly relevant to human disease.”

“Regulus has an impressive track record of executing on innovation in the field of microRNA therapeutics,” said Max Wallace, Chief Executive Officer, ABC². “The combination of Regulus’ expertise in microRNA therapeutics with Samsung’s preclinical GBM models compelled us to support this promising collaborative approach.”

Glioblastoma multiforme, also known as glioblastoma or grade IV astrocytoma, is a fast growing brain tumor that forms from glial (supportive) tissue of the brain.  GBM is the most prevalent form of primary brain tumor and peak incidence is in adults between 45 and 70 years.  Treatment options are limited and survival is little over one year. GBM is considered a rare, or orphan, disease with an incidence in the U.S. of approximately 12,000 per year.

Regulus is advancing multiple microRNA therapeutic programs to the clinic in the areas of fibrosis, HCV infection, immuno-inflammatory disease, metabolic disease, and oncology.

 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. 

 About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx.

 Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting microRNAs for GBM. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

LA JOLLA, Calif., Nov. 8, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced presentations on its preclinical programs for the treatment of fibrosis at the American Association of Nephrology “Kidney Week” Annual Meeting held Nov. 8–13, 2011, in Philadelphia. New data will be presented demonstrating that microRNA-21 (miR-21) is upregulated in human patients and animal models with kidney injury and fibrosis. In preclinical models, genetic deletion of miR-21 or pharmacologic inhibition using proprietary anti-miR oligonucleotides decreased fibrotic gene expression and improved kidney fibrosis. These new data demonstrate that miR-21 contributes to fibrosis and epithelial injury in the kidney, and supports the development of anti-miR-21 oligonucleotides as a therapeutic approach for treating chronic kidney disease.

 “In collaboration with Dr. Jeremy S. Duffield, M.D., Ph.D., University of Washington, we have shown that inhibition of miR-21 with our proprietary anti-miR oligonucleotides is effective at preventing kidney fibrosis in animal models. We are working with our partners at Sanofi to select optimal anti-miR-21 oligonucleotides to move forward into clinical development,” said Neil W. Gibson, Ph.D. Chief Scientific Officer of Regulus Therapeutics. “Fibrosis is a key contributor to several disease conditions having limited treatment options, and anti-miR oligonucleotides targeting miR-21 provide a promising innovative approach to this significant unmet medical need.”  

“The kidney acts as the body’s natural filter of blood, removing waste products, toxins and producing urine.  As such, the kidney is particularly susceptible to fibrosis because of its highly unusual vascular bed and susceptibility to tissue ischemia. The causes of kidney fibrosis are many including diabetes and hypertension, as well as acute injuries to the kidney such as IgA nephropathy, a common form of inflammation of the glomeruli, or as the result of organ transplant,” said Dr. Duffield, M.D., Ph.D. Associate Professor of Medicine, in the Division of Nephrology, at the University of Washington. “In our work with Regulus, we have identified microRNA signatures in kidney injury and fibrosis in both animal models and human disease. Our results strongly suggest that miR-21 contributes to the pathogenesis of kidney injury and fibrosis, and inhibition with anti-miR-21 oligonucleotides may be useful as a treatment of chronic kidney diseases in humans.”

Regulus controls fundamental patent rights related to miR-21, including compositions of matter for the miR-21sequence and complement covered in the Tuschl III patent series. Additional Regulus patent rights include compositions of matter for various chemically modified anti-miR-21 oligonucleotides and methods of use for the treatment of fibrosis with anti-miR-21.

Regulus is advancing multiple microRNA therapeutic programs to the clinic in the areas of fibrosis, HCV infection, immuno-inflammatory disease, metabolic disease, and oncology. The miR-21 program is partnered with Sanofi and together we are advancing anti-miR-21 toward the clinic.

 Regulus will have two oral presentations at Kidney Week:

 1. B. Nelson Chau, Ph.D. Associate Director at Regulus will be giving the lecture “microRNA Therapeutics” on November 9th, 2011 at 3:00pm as part of a focused Early Session: Advances in Research Conference: MicroRNA. 

 2. Deidre MacKenna, Ph.D. Director at Regulus will be giving an oral presentation entitled: “Inhibition of microRNA-21 as a Therapeutic Strategy for Kidney Fibrosis” on November 12^th, 2011 at 4:30pm as part of the session on “Tubular Injury and Fibrosis: Starting and Stopping”.

Data that will be presented include the demonstration that miR-21 is upregulated in kidney injury and fibrosis in both preclinical mouse models and human patients. Regulus and collaborators used two well-characterized preclinical mouse models of kidney damage: unilateral ureteral obstruction (UUO) and unilateral ischemia reperfusion injury (IRI) models. miR-21 was highly expressed in normal kidney and was further induced in response to either UUO or IRI. In humans, miR-21 was upregulated in biopsies from kidney transplant patients with histological markers of acute kidney injury (AKI) and chronic allograft nephropathy (CAN). To further understand the role of miR-21 in the preclinical models, miR-21 deficient mice were characterized and found to be healthy, fertile, and have normal body weight. Additionally, these mice were resistant to fibrosis induced in either the UUO or IRI models. The results were recapitulated in the UUO model using anti-miR-21 oligonucleotides administered prophylactically. The mice treated with anti-miR-21 had improved fibrosis as judged both by histology or fibrotic gene expression. Gene expression data from kidneys of wildtype and miR-21 knockout mice identified about 700 genes that appear to be regulated by miR-21, including genes involved in metabolic pathways such as PPAR (peroxisome proliferator-activated receptor alpha).  PPAR is a central transcription factor that regulates a number of lipid oxidation and metabolism pathways. Genetic manipulation of PPAR expression further validated the role of miR-21 in UUO induced fibrosis.  Mice lacking PPAR were not protected by anti-miR-21 treatment, while those that expressed PPAR specifically in the proximal tubule epithelium were protected.  Induction of PPAR appears to participate in the protective effects of anti-miR-21 treatment, potentially through protection of the epithelial tubule injury and repair processes. These studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney, and is a candidate target for anti-fibrotic therapy.

 About microRNAs

The discovery of microRNAin 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.  

About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The companyworks with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx.

 Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting miR-21. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

LA JOLLA, Calif., Nov. 2, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that the Australian Patent Office has recently granted claims in the ‘Sarnow’ patent series for microRNA-122 (miR-122) therapy in the treatment of hepatitis C viral (HCV) infections. The granted claims in Australia extend the reach of the Sarnow patent estate that already covers the use of an anti-miR inhibitor of miR-122 for the treatment of HCV in the United States and Europe. The Sarnow patent series, owned by Stanford University, has been exclusively licensed to Regulus and covers any compound that targets miR-122 for the treatment of HCV in the United States, Europe, and Australia. 

Regulus controls a comprehensive and dominant patent estate related to microRNA therapeutics, including miR-122 therapeutic agents. Specifically for miR-122, Regulus controls the following:

• The ‘Sarnow’ patent estate claiming the use of anti-miR-122 to treat HCV infection, as a single therapeutic agent or in combination with other HCV therapeutic agents (US Patent No. 7,307,067; US Patent No. 7,838,504; EP Patent No. 1 747 023; and Australian Patent Application No. 2005240118 recently accepted for grant);
• The ‘Esau’ patent claiming the use of anti-miRs targeting miR-122 as inhibitory agents (US Patent No. 7,683,036);
• The ‘Tuschl III’ patent claiming compositions of matter for miR-122 and complementary oligonucleotides (US Patent No. 7,232,806);
• The ‘Manoharan’ patent claiming antagomirs, including antagomirs targeting miR-122 (US Patent No. 7,582,744); and
• A Regulus-owned European patent claiming the use of miR-122 antagonists for reducing cholesterol (EP 1 931 782).

“We are pleased with the recent allowance of miR-122 claims in Australia following issuances in Europe and the United States. This further exemplifies Regulus’ leading intellectual property portfolio in the field of microRNA therapeutics. Recent clinical data in the field has demonstrated that inhibiting miR-122 with an oligonucleotide is safe, well tolerated, and able to reduce viral titers. That data, in combination with Regulus’ data demonstrating potent inhibition with a proprietary anti-miR having favorable pharmacokinetic properties, supports the development of anti-miR-122 for the treatment of HCV in combination with other anti-virals,” said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus Therapeutics. “The HCV landscape has undergone a tremendous amount of transformation with the recent emergence of new direct-acting antivirals.  Anti-miR-122 is attractively positioned because it targets a host factor that is essential for viral replication and therefore may be resistant to viral mutation and escape.”

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 (Jopling et al. (2005) Science 309, 1577-81). In earlier work, scientists at Alnylam Pharmaceuticals and Isis Pharmaceuticals (Regulus’ co-founders) demonstrated the ability to antagonize miR-122 in vivo using chemically modified single-stranded anti-miR oligonucleotides. Data from multiple preclinical studies have shown a robust HCV antiviral effect following inhibition of miR-122.  In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection.

Regulus is advancing multiple other microRNA therapeutic programs to the clinic in the areas of fibrosis, immuno-inflammatory disease, metabolic disease, and oncology.

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. To learn more about microRNAs, please visit http://www.regulusrx.com/microrna/microrna-explained.php.

About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and Sanofi entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis.

For more information, please visit http://www.regulusrx.com. Regulus is also on YouTube at http://www.youtube.com/user/RegulusRx#p/f and on Twitter at www.twitter.com/regulusrx.

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting miR-122. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

LA JOLLA, Calif., October 24, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, will host this week a webinar that focuses on the potential of microRNA-33 as a target for the treatment of atherosclerosis. The discussion will involve pre-clinical research findings that demonstrate microRNA-33’s key role in cholesterol homeostasis and fatty acid metabolism. These findings were published last week in Nature (Rayner et al., Nature, October 20, 2011).

Date: Wednesday, October 26, 2011

Time:   11 a.m. EDT

Place: http://www.videonewswire.com/event.asp?id=82015

Presenters and Topics

- Neil Gibson, Ph.D., Chief Scientific Officer at Regulus Therapeutics, will discuss microRNAs and why microRNA therapeutics represent a new class of innovative, high-impact medicines.

- Kathryn Moore, Ph.D., Associate Professor in the Department of Medicine at NYU Langone Medical Center, will highlight the new preclinical data on targeting microRNA-33 for the treatment of cardiovascular disease.

- Hubert Chen, M.D., Vice President Translational Medicine at Regulus Therapeutics, will discuss the next steps and clinical opportunities for targeting microRNA-33.

The discussion will be moderated by Zachary Zimmerman, Ph.D., Director Business Development at Regulus Therapeutics.

To participate in the webinar, please register at http://www.videonewswire.com/event.asp?id=82015. Questions for the panelists may be submitted online during the live event. Please connect to the webinar 15 min. prior to the start time to ensure adequate time for registration and to download any software that may be necessary.

Windows Media Player software is downloadable free from http://www.microsoft.com and at least a 56Kbps connection to the internet is required. If you experience problems listening to the webinar, please send an e-mail to: webcast@multivu.com.

About microRNA-33a/b

microRNA-33a and b (miR-33a/b), which differ by only two nucleotides, are intronic microRNAs located  within the sterol response element binding protein genes SREBF2 and SREBF1, respectively, which code for transcription factors that regulate cholesterol homeostasis and fatty acid metabolism. Recent studies have shown that miR-33a/b regulates the cholesterol and fatty acid pathways in a negative feedback loop.  miR-33a/b represses the cholesterol transporter ABCA1 in hepatocytes and macrophages resulting in decreased cellular cholesterol efflux to apoA1, a key step in the generation of HDL-C and reverse cholesterol transport. Inhibition of miR-33 in mice, which only have miR-33a, resulted in an increase in expression of ABCA1 protein and increase in cholesterol efflux resulting in a reduction of atherosclerotic plaques (Rayner et al., J Clin Invest. 2011). In addition, miR-33a/b suppresses key enzymes involved in the oxidation of fatty acids resulting in the accumulation of triglyceride. Inhibition of miR-33a/b increases fatty acid oxidation and insulin signaling (Davalos et al., PNAS. 2011). These studies suggest that an anti-miR33a/b oligonucleotide treatment may be a promising strategy to treat atherosclerosis.

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. To learn more about microRNAs, please visit http://www.regulusrx.com/microrna/microrna-explained.php.

About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis. For more information, please visit http://www.regulusrx.com.

Click here to view video segments about microRNA therapeutics and Regulus featuring the company’s executives http://www.youtube.com/user/RegulusRx#p/f

Click here to follow Regulus on Twitter at www.twitter.com/regulusrx.

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting miR-33a/b. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

microRNA-33a/b for atherosclerosis –

- Company to host webinar on October 26, 2011 to discuss findings -

LA JOLLA, Calif., October 20, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, and collaborators at NYU Langone Medical Center and Wake Forest Baptist Medical Center today announced the publication of new pre-clinical research findings in the journal Nature (Rayner et al., Nature, October 20, 2011). The new data show the first demonstration of marked increases in high density lipoprotein cholesterol (HDL-C), the ‘good’ cholesterol, and suppression of plasma triglyceride levels in non-human primates through inhibition of both microRNA-33a and microRNA-33b (miR-33a/b) with proprietary chemically modified anti-miR oligonucleotides. A webinar to discuss the new data will be hosted by Regulus and features Kathryn Moore, Ph.D., associate professor in the Department of Medicine at NYU Langone Medical Center and Regulus scientists (11:00am EDT, October 26, 2011).

“In addition to atherosclerotic plaque regression and enhanced reverse cholesterol transport that we previously observed in rodents with our collaborators at NYU Langone Medical Center, anti-miR-33 treatment is now shown to increase HDL cholesterol and lower triglycerides in non-human primates,” said Hubert C. Chen, M.D., Vice President of Translational Medicine at Regulus. “These combined data sets provide strong evidence that an anti-miR-33 therapeutic approach can offer multiple mechanisms to benefit patients with atherosclerosis. Anti-miR-33a/b is one of several microRNA therapeutic programs we are advancing toward clinical development.”

Dr. Moore said, “The current study is the first to demonstrate in non-human primates that inhibition of miR-33a/b can both increase circulating levels of HDL-C and suppress plasma triglyceride levels. This study highlights the benefits of modulating miR-33a/b and their downstream metabolic pathways.”

The Nature paper, “Inhibition of miR-33a/b in non-human primates raises plasma HDL cholesterol and reduces VLDL triglycerides,” showed that systemic delivery of an anti-miR targeting both miR-33a and miR-33b in non-human primates increased hepatic miR-33 target gene expression and induced a sustained increase in plasma HDL-C over the 12-week study. In the study protocol, six animals per group received anti-miR-33 via subcutaneous injection at a clinically relevant dose of five mg/kg or a mismatch control. The anti-miR or control were formulated in saline, and administered twice weekly for the first two weeks, and then weekly for the remainder of the 12-week study.  Results showed a maximal HDL-C increase of 50% after eight weeks that was sustained throughout the remainder of the study. Anti-miR-33a/b treatment in this model also increased the expression of miR-33 target genes involved in fatty acid oxidation resulting in suppressed triglyceride levels, a finding not previously observed in mice. The decrease in triglycerides was apparent after four weeks and reached a maximum reduction of 50%.  This pre-clinical study was the first to demonstrate that inhibiting miR-33a/b has a profound and sustained effect on both circulating HDL-C and plasma triglyceride levels.

Ryan Temel, Ph.D., assistant professor at Wake Forest Baptist Medical Center, said, “anti-miR-33a/b has the potential to treat multiple aspects of metabolic syndrome which is a group of risk factors that increase the risk for coronary artery disease, stroke, and type 2 diabetes.”

Multiple studies have demonstrated that miR-33a/b strongly represses the cholesterol transporter ABCA1, resulting in decreased generation of HDL-C and reverse cholesterol transport (Rayner et al., J Clin Invest. 2011) as well as key enzymes involved in the oxidation of fatty acid resulting in the accumulation of triglycerides (Davalos et al., PNAS. 2011).  These findings indicate that miR-33a and miR-33b are key regulators of cholesterol and fatty acid metabolism, and that an anti-miR-33 approach can directly impact atherosclerosis, as well as address important cardiovascular risk factors such as obesity, insulin resistance, and hypertriglyceridemia.

Regulus is developing microRNA therapeutics targeting miR-33a/b. The company controls fundamental patent rights related to miR-33a/b, including the miR-33a/b 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-33a/b compounds and methods of use for the treatment of cardiovascular diseases with anti-miR-33a/b.

Webinar to be held on October 26, 2011

Dr. Moore and Regulus scientists, Drs. Neil Gibson, Ph.D., Chief Scientific Officer, Hubert Chen, M.D., and Christine Esau, Ph.D., Associate Director Metabolic Disease, will present the data published in Nature and discuss the data’s implications in a webinar scheduled for 11:00am EDT on October 26, 2011. To participate in the webinar, register at http://www.videonewswire.com/event.asp?id=82015. Please connect to the webinar several minutes prior to the start time to ensure adequate time for any software download that may be necessary. Questions for the panelists may be submitted during the live event through the web portal. The webinar will be available for replay on the Regulus website at http://www.regulusrx.com.

About microRNA-33a/b

microRNA-33a and b (miR-33a/b), which differ by only two nucleotides, are intronic microRNAs located  within the sterol response element binding protein genes SREBF2 and SREBF1, respectively, which code for transcription factors that regulate cholesterol homeostasis and fatty acid metabolism. Recent studies have shown that miR-33a/b regulates the cholesterol and fatty acid pathways in a negative feedback loop.  miR-33a/b represses the cholesterol transporter ABCA1 in hepatocytes and macrophages resulting in decreased cellular cholesterol efflux to apoA1, a key step in the generation of HDL-C and reverse cholesterol transport. Inhibition of miR-33 in mice, which only have miR-33a, resulted in an increase in expression of ABCA1 protein and increase in cholesterol efflux resulting in a reduction of atherosclerotic plaques (Rayner et al., J Clin Invest. 2011). In addition, miR-33a/b suppresses key enzymes involved in the oxidation of fatty acids resulting in the accumulation of triglyceride. Inhibition of miR-33a/b increases fatty acid oxidation and insulin signaling (Davalos et al., PNAS. 2011). These studies suggest that an anti-miR33a/b oligonucleotide treatment may be a promising strategy to treat atherosclerosis.

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. To learn more about microRNAs, please visit http://www.regulusrx.com/microrna/microrna-explained.php.

About Regulus Therapeutics, Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. The company works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics toward clinical development in several areas, including fibrosis, hepatitis C, immuno-inflammatory diseases, metabolic diseases and oncology. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics with an initial focus on fibrosis. For more information, please visit http://www.regulusrx.com.

Click here to view video segments about microRNA therapeutics and Regulus featuring the company’s executives http://www.youtube.com/user/RegulusRx#p/f

Click here to follow Regulus on Twitter at www.twitter.com/regulusrx.

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting miR-33a/b. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’, Alnylam’s, and Isis’ programs are described in additional detail in Alnylam’s and Isis’ annual reports on Form 10-K for the year ended December 31, 2010, and its most recent quarterly report on Form 10-Q.  Copies of these and other documents are available from Alnylam or Isis.

Regulus Therapeutics Inc. is a biopharmaceutical company leading the discovery and development of innovative new medicines based on microRNAs. Regulus is advancing microRNA therapeutics across several key areas, including fibrosis, immuno-inflammatory diseases, metabolic diseases, oncology and HCV.  In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics for the treatment of HCV.  In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics.

Regulus is located in Torrey Pines, California and has a seasoned executive team experienced in corporate management, business, science, drug discovery and development. Regulus’ scientific advisory board consists of world-class scientists and some of the foremost authorities in the field of microRNA research.

We are currently seeking a highly motivated Director/Senior Director of Project Management to be part of a unique and exciting opportunity in drug discovery. For more information, visit www.RegulusRx.com.

Requirements

Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects¹. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention². MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3–5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels^3, 4, 5 and providing protection against atherosclerosis⁶; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in theSREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.

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