Design, synthesis and in vivo results of chemically-modified antisense oligonucleotides targeting microRNA-122

MEDI 288

Garth A. Kinberger1, Stephanie Propp2, Scott Davis2, Susan Freier2, Christine Esau2, Eric E. Swayze, eswayze@isisph.com1, C. Frank Bennett3, and Balkrishen Bhat1. (1) Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc, 1891 Rutherford Road, Carlsbad, CA 92008, (2) Department of Biology, Isis Pharmaceuticals, Inc, 1896 Rutherford Road, Carlsbad, CA 92008, (3) Isis Pharmaceuticals, Inc, 1896 Rutherford Road, Carlsbad, CA 92008
MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression during development by binding to the 3'-untranslated region of the mRNA and inhibiting translation. The most abundant microRNA in liver is miR-122. Using an antisense oligonucleotide (ASO) to inhibit miR-122 in normal and diet induced obesity mouse models we showed reduction in cholesterol synthesis and improvement in liver steatosis, respectively. These data point to miR-122 as a potential therapeutic target for the treatment of cardiovascular disease. To further improve in vivo activity, a number of antimiR-122 ASOs consisting of modifications in sugar, heterocycle and backbone were designed and synthesized, and their ability to inhibit miR-122 activity were evaluated. SAR studies resulted in molecules that displayed an earlier onset of action as well as several fold increase in activity compared to parent uniform 2'-O-MOE modified ASO. The results from the miR-122 SAR will be presented.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007