| abstract |
The present invention relates to conjugated antisense compounds which act as prodrugs targeting Apolipoprotein C-III (ApoCIII), and methods of decreasing ApoCIII mRNA and protein expression. Antisense compounds can be siRNAs or antisense oligonucleotides, preferably 12-20 nucleosides in length, and can be modified with phosphodiester internucleoside linkages or by incorporating a modified sugar. These compounds are modified with a conjugate group, preferably N-acetyl galactosamine (GalNAc), wherein the conjugate group comprises a cleavable moiety that assists the antisense compound gaining entry to the cell, but should be subsequently cleaved and not interfere with RNase H interactions with the antisense compound. Conjugate groups are also preferably bound to the 5' end of the antisense compound for improved activity and cleavage. Conjugate compounds are used in therapy of disease associated with increased ApoCIII levels, including cardiovascular, metabolic and inflammatory disorders, for example pancreatitis, and for reducing triglyceride levels or increasing HDL levels in the subject. |