iRNA AGENTS WITH BIOCLEAVABLE TETHERS

摘要

The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose that further includes a tether having one or more linking groups, in which at least one of the linking groups is a cleavable linking group. The tether in turn can be connected to a selected moiety, e.g., a ligand, e.g., a targeting or delivery moiety, or a moiety which alters a physical property. The cleavable linking group is one which is sufficiently stable outside the cell such that it allows targeting of a therapeutically beneficial amount of an iRNA agent (e.g., a single stranded or double stranded iRNA agent), coupled by way of the cleavable linking group to a targeting agent—to targets cells, but which upon entry into a target cell is cleaved to release the iRNA agent from the targeting agent.

主权项

1. A bio-cleavable oligonucleotide-ligand conjugate represented by the following formula: wherein: NA is a chemically modified or unmodified oligonucleotide; L is a ligand selected from the group consisting of a multivalent galactose and a multivalent N-acetyl-galactosamine;represents a tether comprising one or more linking groups having a cleavable disulfide group (—SS—), wherein each linking group is either present or absent;
is a cyclic or acyclic carrier moiety; X is a chemical linkage between the ligand L and the tether; Y is a chemical linkage between the tether and the ; and Z is a chemical linkage between the and the oligonucleotide NA.