Document Detail


Unique MOE-DNA chimeric oligonucleotide induces an atypical MDA5 dependent induction of type I interferon response.
MedLine Citation:
PMID:  22505629     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Antisense oligonucleotides (ASO) containing 2'-O-methoxyethylribose (2'-MOE) modifications have been shown to possess both excellent pharmacokinetic properties and robust pharmacological activity in several animal models of human disease. 2'-MOE ASOs are generally well tolerated displaying minimal to mild proinflammatory effect at doses far exceeding therapeutic doses. While the vast majority of 2'-MOE ASOs are safe and well tolerated, a small subset of ASO inducing acute inflammation in mice has been identified. The mechanism for these findings is not clear at this point, but the effects are clearly sequence-specific. One of those ASO, ISIS 147420, causes a severe inflammatory response atypical of this class of oligonucleotides characterized by induction in interferon-β at 48 hours followed by acute transaminitis and extensive hepatocyte apoptosis and necrosis at 72 hours. A large number of interferon stimulated genes (ISGs) were significantly upregulated in liver as early as 24 hours. We speculated that a specific sequence motif might cause ISIS 147420 to be mistaken for viral RNA or DNA thus triggering an acute innate immune response. ISIS 147420 toxicity was independent of Toll-like receptors as there was no decrease in IFN-β in TRIF or Myd88 deficient mice. The involvement of cytosolic RIG-I-like pattern recognition receptors was also investigated. Pretreatment of mice with MDA5 and IPS-1 ASO, but not RIG-I or LGP2 ASO, prevented the increase in IFN-β and ALT induced by ISIS 147420. These results revealed a novel mechanism of oligonucleotide mediated toxicity requiring both MDA5 and IPS-1 and resulting in activation of the innate immune response.
Authors:
Sebastien A Burel; Todd Machemer; Frank L Ragone; Hiroki Kato; Patrick Cauntay; Sarah Greenlee; Aneeza Salim; William A Gaarde; Gene Hung; Raechel Peralta; Susan M Freier; Scott P Henry
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-13
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  -     ISSN:  1521-0103     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 ISIS Pharmaceuticals;
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