Vol. 303, Issue 3, 1145-1154, December 2002

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

Ian Popoff¹ , Humberto Jijon, Brett Monia, Michele Tavernini, Michael Ma, Rob McKay and Karen Madsen

Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada (I.P., H.J., M.T., M.M., K.M.) and ISIS Pharmaceuticals, Carlsbad, California (B.M., R.M.)

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.