Alnylam And Collaborators Publish Research On The Immunostimulatory Properties And Mechanisms Of Certain siRNAs In Mammalian Cells
Cambridge, MA - Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced the publication of a study in the Journal of Interferon & Cytokine Research by scientists at Alnylam Europe (now Roche Kulmbach), and collaborators, further delineating the mechanisms whereby some siRNAs can trigger immunostimulatory effects in mammalian cells. In addition, this research demonstrates the ability to select or chemically modify siRNAs to avoid such effects.
In the study (Zamanian-Daryoush et al, Journal of Interferon & Cytokine Research 28, 221-233 (2008)), certain siRNAs were shown to induce tumor necrosis factor (TNF)-alpha and/or interferon alpha (IFN-alpha) release in human cells in vitro. These data also demonstrated that the TNF-alpha-related immunostimulatory effects were not always coupled to the previously identified ability of certain siRNAs to induce IFN-alpha expression. These new findings show that cell-based screening and/or certain chemical modifications of siRNAs can be used to eliminate both the IFN-alpha and TNF-alpha immunostimulatory responses in these assays.
"This new study continues to expand Alnylam's scientific leadership in the field of RNAi research as it represents continued understanding and refinement of our discovery process where ‘drug-like' properties of siRNAs can be readily achieved," said Rachel Meyers, Ph.D., Senior Director of RNAi Lead Discovery at Alnylam. "Indeed, Alnylam applies rigorous scientific methods and controls to ensure siRNA pharmacology with the expected and desired mechanism of action. These methods include selection of siRNAs lacking immunostimulatory properties in vitro as well as in vivo analyses to confirm specific RNAi activity, such as the use of siRNA mismatch controls and 5' RACE-mediated detection of RNAi-specific mRNA cleavage products."
Alnylam has previously published data in the journal Nature Medicine (Hornung et al., Nature Medicine 11, 263-70 (2005)) highlighting the presence of toll-like receptor (TLR)-dependent IFN-inducing stimulatory sequence motifs in certain siRNAs. Additional studies showed that so-called "blunt-ended" siRNAs can stimulate IFN-alpha expression by activation of the retinoic acid-inducible gene (RIG-I) pathway (Marques et al., Nature Biotechnology 24, 559-65 (2006)). As demonstrated in the current publication, certain siRNAs can stimulate production of TNF-alpha in vitro in a manner suggestive of recruitment of a different TLR and in an siRNA sequence-dependent manner. In aggregate, these findings highlight the importance of RNAi lead discovery efforts that select and screen for siRNA lacking such immunostimulatory properties.
About RNA Interference (RNAi)
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. RNAi therapeutics target the cause of diseases by potently silencing specific messenger RNAs (mRNAs), thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including hypercholesterolemia, liver cancers, and Huntington's disease. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, and Roche. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam has established "RNAi 2010" which includes the company's plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam is a joint owner of Regulus Therapeutics LLC, a joint venture focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts.
SOURCE: Alnylam Pharmaceuticals, Inc.