PT  - JOURNAL ARTICLE
AU  - Ian Popoff
AU  - Humberto Jijon
AU  - Brett Monia
AU  - Michele Tavernini
AU  - Michael Ma
AU  - Rob McKay
AU  - Karen Madsen
TI  - Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice
AID  - 10.1124/jpet.102.039768
DP  - 2002 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1145--1154
VI  - 303
IP  - 3
4099  - http://jpet.aspetjournals.org/content/303/3/1145.short
4100  - http://jpet.aspetjournals.org/content/303/3/1145.full
SO  - J Pharmacol Exp Ther2002 Dec 01; 303
AB  - poly(ADP-ribose) polymerase-2 (PARP-2) is a newly described member of the PARP family of nuclear enzymes. Previous studies have shown pharmacological inhibition of PARP activity to have a beneficial role in attenuating inflammation. We developed a chemically modified 2′-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 110251) inhibitor of PARP-2 and tested it for efficacy in the interleukin (IL)-10-deficient mouse. In tissue culture, ISIS 110251 reduced PARP-2 mRNA expression in a concentration- and sequence-specific manner. In 129 Sv/Ev mice, ISIS 110251 reduced PARP-2 mRNA in liver by 80%. This reduction was dependent upon treatment duration and was independent of the method of delivery. In interleukin-10-deficient mice with established colitis, treatment with ISIS 110251 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitric-oxide synthase activity, and attenuated inflammation. Our data demonstrate that selective inhibition of PARP-2 activity results in a marked improvement of colonic inflammatory disease in a mouse model of chronic colitis and a normalization of colonic function.