ASOs are single-stranded deoxyribonucleotides corresponding to a specifi c mRNA sequence. ASOs bind to mRNA by Watson-Crick hybridization, inducing selective degradation of the mRNA.|
This process is largely mediated by RNase-H, an enzyme that cleaves the RNA strand of a DNA/RNA duplex, resulting in knockout of the encoded protein . ISIS 301012 is an ASO that inhibits the production of apo B100. Mutations in apo B, which result in enhanced catabolism of apo B or reduced translation or secretion, are associated with reduced plasma LDL-C and reduced risk of CVD . Apo B antisense has been shown to effectively decrease the synthesis of apo B100 and to reduce plasma levels of apo B and LDLC. The mouse-specifi c apo B antisense, ISIS 147764, was tested in several murine models, including C57BL/6 mice fed a high-fat diet, apo E–defi cient mice, and Ldlrdefi cient mice. Administering ISIS 147764 resulted in a dose- and time-dependent decrease in hepatic apo B100 mRNA levels and serum apo B100 levels, together with a 25% to 55% decrease in total cholesterol (25% to 55%) and a 40% to 88% decrease in LDL-C .
ISIS 301012 was fi rst studied in human apo B100 transgenic mice. Administering this ASO to LDL receptor–deficient human apo B100 transgenic mice for 14 weeks reduced human apo B100 liver mRNA by 89% and serum apo B100 levels by 68%. Additionally, circulating infl ammatory cytokines and atherosclerotic plaque volume decreased .