Modified iRNA agents
View Patent ↗The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose. The inclusion of such a monomer can allow for modulation of a property of the iRNA agent into which it is incorporated, e.g., by using the non-ribose moiety as a point to which a ligand or other entity, e.g., a lipophilic moiety. e.g., cholesterol, is directly, or indirectly, tethered. The invention also relates to methods of making and using such modified iRNA agents.
1. A modified RNA agent comprising a sense strand and an antisense strand, wherein one or more ribose replacement modification subunit (RRMS) comprising a ligand is incorporated into at least one of said strands, wherein the RRMS is a cyclic carrier selected from the group consisting of hydroxyproline, piperidine, morpholine, piperazine, and decalin, and wherein the ligand is connected to the RRMS via a linker of C 1 -C 20 alkyl substituted with NR c R d , NHC(O)R d , C(O)R d , or C(O)OR d , wherein R c is H or C 1 -C 6 alkyl; and R d is the ligand.
2. The modified RNA agent of claim 1 , wherein the RRMS is incorporated into the sense strand.
3. The modified RNA agent of claim 2 , wherein the RRMS is incorporated into the 3′ end of the sense strand.
4. The modified RNA agent of claim 3 , wherein the RRMS is placed within 1, 2, or 3 positions of the 3′ end of the sense strand.
5. The modified RNA agent of claim 1 , wherein the RRMS is incorporated into the antisense strand.
6. The modified RNA agent of claim 5 , wherein the RRMS is incorporated into the 3′ end of the antisense strand.
7. The modified RNA agent of claim 1 , wherein the sense strand and the antisense strand are independently 17 to 25 nucleotides in length.
8. The modified RNA agent of claim 1 , wherein the modified RNA agent includes a duplex region between 17 and 23 pairs in length.
9. The modified RNA agent of claim 1 , wherein the modified RNA agent includes at least one 3′ overhang of 2-3 nucleotides in length.
10. The modified RNA agent of claim 1 , wherein the ligand alters the distribution, targeting or lifetime of a RNA agent into which it is incorporated.
11. The modified RNA agent of claim 1 , wherein the ligand is selected from the group consisting of a folic acid radical; a steroid radical; a carbohydrate radical; a vitamin A radical; a vitamin E radical; and a vitamin K radical.
12. The modified RNA agent of claim 1 , wherein the ligand is a cholesterol radical.
13. The modified RNA agent of claim 1 , wherein the ligand is a carbohydrate radical.
14. The modified RNA agent of claim 1 , wherein the ligand is a targeting group selected from the group consisting of mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, and an RGD peptide or RGD peptide mimetic.
15. The modified RNA agent of claim 1 , wherein at least two RRMS subunits are incorporated into at least one of said strands.
16. The modified RNA agent of claim 15 , wherein at least two RRMS subunits are incorporated into the sense strand.
17. The modified RNA agent of claim 15 , wherein at least two RRMS subunits are incorporated into the antisense strand.