Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today 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.
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