Compounds and methods for modulating expression of DGAT2

摘要

The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.

主权项

1. A short antisense compound 8 to 14 monomers in length, comprising a 2′-deoxyribonucleotide gap region flanked on each side by a wing, wherein each wing independently comprises 1 to 3 high-affinity modified monomers, wherein the short antisense compound has a motif selected from the group consisting of 1-12-1, 1-1-10-2, 2-10-1-1, 2-10-2, 1-10-1, 1-10-2, 3-8-3, 2-8-2, 1-8-1, 3-6-3, and 1-6-1, and wherein the short antisense compound is targeted to a nucleic acid (SEQ ID NO: 10) encoding diacylglycerol O-acyltransferase 2 (DGAT2) in the liver.