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New Findings Demonstrate Therapeutic Benefit of Anti-MicroRNA-21

Regulus Therapeutics LLC, a joint venture between Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) and Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) formed to discover, develop, and commercialize microRNA-based therapeutics, announced today the publication of new research in the journal Nature on the role of a microRNA, known as miR-21, in heart failure(1). The new findings demonstrated that miR-21 is over-expressed in the failing human heart and contributes to heart failure through its regulation of a stress-response signaling pathway associated with changes in heart muscle structure and function. The study went on to demonstrate that targeting miR-21 with an anti-miR-21, antisense oligonucleotide (also called an "antagomir") prevented heart failure in mouse models. Furthermore, administration of anti-miR-21 after established heart failure resulted in a significant treatment benefit in the animal model.

"We view this new study as a landmark event in the advancement of microRNA therapeutics as a new class of innovative medicines. Indeed, we believe that this is the first study to clearly demonstrate therapeutic efficacy for targeting microRNAs in an animal model of human disease," said Kleanthis G. Xanthopoulos, Ph.D., President and Chief Executive Officer of Regulus Therapeutics. "Moreover, these exciting data highlight microRNA-based therapeutics specifically targeting miR-21 as a promising approach for the treatment of heart failure, extending the scope of disease opportunities for Regulus."

"Heart failure remains a major cause of morbidity and mortality across the world. Despite decades of clinical research, and some important advances in pharmacologic and device therapy, future development of new high-impact medicines can only emerge with a better understanding of molecular mechanisms in the cause or pathway of this disease," said Eugene Braunwald, M.D., Distinguished Hersey Professor of Medicine at Harvard Medical School, and Chairman, TIMI Study Group at Brigham and Women's Hospital. "This exciting research defines an entirely new potential strategy for intervention, where antagonism of a single microRNA could result in correction of the disease pathways of heart failure."

Heart failure, also known as congestive heart failure (CHF), is a condition where the heart is unable to supply adequate flow of blood to the body's organs and is caused by significant or prolonged stress to the heart. CHF can occur following a heart attack, certain infections, hypertension, and through genetic causes, and affects approximately five million patients in the U.S.; CHF accounts for substantial morbidity and mortality with approximately 600,000 deaths annually.

microRNAs have been described previously as being involved in the regulation of gene expression as part of heart physiology and development,(2,3) but their exact role in disease and their validity as targets for intervention have remained undetermined. In this new study, miR-21 was discovered to be expressed in fibroblast cells of the heart, with increased levels in mouse models of heart failure and also in human disease tissue. Increased expression of miR-21 was shown to regulate a previously unrecognized stress-response pathway in fibroblasts involving the gene sprouty-1 and the MAP-kinase signaling pathway. In turn, increased MAP-kinase signaling promoted enhanced fibroblast survival, increased secretion of certain factors (e.g., fibroblast growth factor) leading to tissue scarring (fibrosis), and cardiac dysfunction including cellular hypertrophy; all hallmark features of the failing human heart.

Treatment with an anti-miR-21 in a mouse model of heart failure was performed using both prevention and treatment protocols. Administration of the anti-miR oligonucleotide resulted in efficient delivery to the heart as measured by fluorescence staining. In a mouse transaortic constriction model of human heart failure, anti-miR-21 treatment silenced increased expression of miR-21 and corrected downstream changes in sprouty-1 and MAP-kinase signaling. Further, treatment with the anti-miR blocked the development of tissue scarring as measured histologically and also reversed the hypertrophy of cardiomyocytes and increased heart weight associated with both the disease model and human disease. Finally, administration of anti-miR-21 corrected defects in the failing heart including left ventricular dilatation and fractional shortening, echocardiographic measurements of heart function. Importantly, anti-miR-21 demonstrated statistically significant improvements in the heart failure animal model when administered prior to, and as long as three weeks after induction of the experimental heart failure.

"This study has revealed a key role for miR-21 in regulating a major stress-response pathway in the failing heart. Administration of anti-miR-21 led to a striking effect in preventing and treating cellular, morphologic, and functional features of heart failure in a well-established animal model," said Peter Linsley, Ph.D., Chief Scientific Officer of Regulus Therapeutics. "Most importantly, these new in vivo data point to the significant potential for targeting microRNAs, where therapeutic impact can be achieved by interrupting entire pathways of disease, not just single disease targets."

The new research was led by the group of Dr. Thomas Thum, affiliated with Dr. Johan Bauersachs' laboratory in the Department for Internal Medicine at the University of Wuerzburg and Carina Gross in the lab of Dr. Stefan Engelhardt at the Virchow Center at the University of Wuerzburg, working in collaboration with scientists at Regulus, Alnylam, University of California, San Francisco, King's College London, Heidelberg University, Northwestern University, and The Rockefeller University.

(1) Thomas Thum, Carina Gross, Jan Fiedler, Thomas Fischer, Stephan Kissler, Markus Bussen, Paolo Galuppo, Steffen Just, Wolfgang Rottbauer, Stefan Frantz, Mirco Castoldi, Juergen Soutschek, Victor Koteliansky, Andreas Rosenwald, M. Albert Basson, Jonathan D. Licht, John T. R. Pena, Sara H. Rouhauifard, Martina U. Muckenthaler, Thomas Tuschl, Gail R. Martin, Johann Bauersachs, & Stefan Engelhardt. microRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature advance online publication, 30 November 2008 (10.1038/nature07511).

(2) Divakaran V, Mann, DL. The emerging role of microRNAs in cardiac remodeling and heart failure. Circulation Research. 2008;103:1072-1083.

(3) Callis, TE, Wang, D. Taking microRNAs to heart. Trends in Molecular Medicine. 2008:14(6) 254-260.

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