title: Unique O-methoxyethyl ribose-DNA chimeric oligonucleotide induces an atypical melanoma differentiation-associated gene 5-dependent induction of type I interferon response.
abstract: Antisense oligonucleotides (ASO) containing 2'-O-methoxyethyl ribose (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. Although the vast majority of 2'-MOE ASOs are safe and well tolerated, a small subset of ASOs 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 ASOs, ISIS 147420, causes a severe inflammatory response atypical of this class of oligonucleotides characterized by induction in interferon-β (IFN-β) at 48 h followed by acute transaminitis and extensive hepatocyte apoptosis and necrosis at 72 h. A large number of interferon-stimulated genes were significantly up-regulated in liver as early as 24 h. 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, because there was no decrease in IFN-β in Toll/interleukin-1 receptor-domain-containing adapter-inducing IFN-β or Myd88-deficient mice. The involvement of cytosolic retinoic acid-inducible gene (RIG)-I-like pattern recognition receptors was also investigated. Pretreatment of mice with melanoma differentiation-associated gene 5 (MDA5) and IFN-β promoter stimulator-1 ASOs, but not RIG-I or laboratory of genetics and physiology 2 (LGP2) ASOs, prevented the increase in IFN-β and alanine aminotransferase induced by ISIS 147420. These results revealed a novel mechanism of oligonucleotide-mediated toxicity requiring both MDA5 and IPS-1 and resulting in the activation of the innate immune response.
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, CA 92010, USA. sburel@isisph.com
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Burel
authors.forename: Todd
authors.initials: T
authors.lastname: Machemer
authors.forename: Frank L
authors.initials: FL
authors.lastname: Ragone
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Patrick
authors.initials: P
authors.lastname: Cauntay
authors.forename: Sarah
authors.initials: S
authors.lastname: Greenlee
authors.forename: Aneeza
authors.initials: A
authors.lastname: Salim
authors.forename: William A
authors.initials: WA
authors.lastname: Gaarde
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Raechel
authors.initials: R
authors.lastname: Peralta
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000410:Alanine Transaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012266:Ribose / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000410:Alanine Transaminase; D053487:DEAD-box RNA Helicases; D004247:DNA; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D016376:Oligonucleotides, Antisense; D017472:Receptors, Interleukin-1; D012266:Ribose; D051193:Toll-Like Receptors; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C510592:Ifih1 protein, mouse