Modification of MyD88 mRNA splicing and inhibition of IL-1beta signaling in cell culture and in mice with a 2'-O-methoxyethyl-modified oligonucleotide.
A number of proinflammatory cytokines, including IL-1beta, signal through the adaptor protein MyD88. This signaling leads to phosphorylation of IL-1R-associated kinase-1 (IRAK-1) and, ultimately, activation of the NF-kappaB transcription factor. A splice variant of MyD88 (MyD88(S)), which lacks the ability to couple IRAK-1 to NF-kappaB, has been described. A chemically modified antisense oligonucleotide (ASO) that alters the splicing ratio of MyD88 to MyD88(S) in both cell culture and in animals has been identified. The ASO (ISIS 337846) binds to exon II donor sites in the MyD88 pre-mRNA. By manipulating levels of MyD88 splicing, proinflammatory signaling through the IL-1R has been shown to be diminished, both in cell culture and in mouse liver. To our knowledge, this represents the first example of modulation of RNA splicing of an endogenous gene target in animals after systemic ASO dosing and suggests that this mechanism may be useful as a novel modulator of inflammatory stimuli.
Vickers
Timothy A
TA
Department of Functional Genomics, Isis Pharmaceuticals, 1896 Rutherfored Road, Carlsbad, CA 92008, USA. tvickers@isisph.com
Zhang
Hong
H
Graham
Mark J
MJ
Lemonidis
Kristina M
KM
Zhao
Chenguang
C
Dean
Nicholas M
NM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016914:Ribonuclease H / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D016914:Ribonuclease H