초록 ▼

The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose.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 m

The invention relates to iRNA agents, which preferably include a monomer in which the ribose moiety has been replaced by a moiety other than ribose.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.

대표청구항 ▼

1. An iRNA agent comprising a first strand and a second strand, wherein at least two subunits having a formula (I) are incorporated into at least one of said strands: wherein: X is N(CO)R7, NR7 or CH2;Y is NR8, O, S, CR9R10, or absent;Z is CR11R12 or absent;each of R1, R2, R3, R4, R9, and R10 is, i

1. An iRNA agent comprising a first strand and a second strand, wherein at least two subunits having a formula (I) are incorporated into at least one of said strands: wherein: X is N(CO)R7, NR7 or CH2;Y is NR8, O, S, CR9R10, or absent;Z is CR11R12 or absent;each of R1, R2, R3, R4, R9, and R10 is, independently, H, ORa, ORb, (CH2)nORa, or (CH2)nORb, provided that at least one of R1, R2, R3, R4, R9, and R10 is ORa or ORb and that at least one of R1, R2, R3, R4, R9, and R10 is (CH2)nORa, or (CH2)nORb;each of R5, R6, R11, and R12 is, independently, H, C1-C6 alkyl optionally substituted with 1-3 R13, or C(O)NHR7; or R5 and R11 together are C3-C8 cycloalkyl optionally substituted with R14;R7 is Rd; or C1-C20 alkyl substituted with NRcRd or NHC(O)Rd;R8 is C1-C6 alkyl;R13 is hydroxy, C1-C4 alkoxy, or halo;R14 is NRcR7;Ra is H or Rb is H or wherein the Strand in each occurrence is independently the first strand or second strand of the iRNA agent; each of A and C is, independently, O or S; andB is OH, O−, or Rc is H or C1-C6 alkyl;Rd is H or a ligand; andn is 1-4. 2. The iRNA agent of claim 1, wherein three subunits having a formula (I) are incorporated into at least one of said strands. 3. The iRNA agent of claim 2, wherein the three subunits having a formula (I) are placed at positions 1, 2 and 3 of the 3′ end of a sense strand. 4. The iRNA agent of claim 1, wherein X is N(CO)R7 or NR7, Y is CR9R10, and Z is absent. 5. The iRNA agent of claim 4, wherein one of R1, R2, R3, R4, R9, and R10 is ORa or ORb; and one of R1, R2, R3, R4, R9, and R10 is (CH2)nORa or (CH2)nORb. 6. The iRNA agent of claim 4, wherein R2, R3, R4, R5, R6, and R10 are H. 7. The iRNA agent of claim 4, wherein R9 is ORa or ORb, and R1 is (CH2)nORa or (CH2)nORb. 8. The iRNA agent of claim 1, R1 can be CH2ORa and R9 can be ORb. 9. The iRNA agent of claim 8, wherein R1 and R9 are cis. 10. The iRNA agent of claim 8, wherein R1 and R9 are trans. 11. The iRNA agent of claim 1, wherein Rd is selected from the group consisting of a folic acid radical, a cholesterol radical, a carbohydrate radical, a vitamin A radical, a vitamin E radical, and a vitamin K radical. 12. The iRNA agent of claim 1, wherein Rd is a cholesterol radical. 13. The iRNA agent of claim 1, wherein Rd is a carbohydrate radical. 14. The iRNA agent of claim 1, wherein Rd is a steroid radical, which is optionally tethered to at least one carbohydrate radical. 15. The iRNA agent of claim 1, wherein at least one of said strands leads to the cleavage of a complementary target sequence via a RISC-dependent mechanism. 16. The iRNA agent of claim 1, wherein A is O in each occurrence. 17. The iRNA agent of claim 1, wherein A is S in at least one occurrence. 18. The iRNA agent of claim 1, wherein formula (I) is incorporated into a sense strand. 19. The iRNA agent of claim 1, wherein formula (I) is incorporated into positions 1, 2 and 3 of the 3′ end of a sense strand. 20. The iRNA agent of claim 1, wherein the iRNA agent is 21 nucleotides in length and has a duplex region of about 19 pairs. 21. The iRNA agent of claim 1, wherein the iRNA agent includes a duplex region between 17 and 23 pairs in length. 22. The iRNA agent of claim 1, wherein Rd is a ligand selected from the group consisting of a lipophile, a lipid, a steroid, a terpene, a vitamin, a carbohydrate, a protein, a protein binding agent, an integrin targeting molecule, polycationic, a peptide or peptide mimic, a polyamine, a dye, an intercalating agent, a cross-linker, a porphyrin, a polycyclic aromatic hydrocarbon, an artificial endonuclease, a lipophilic molecule, a glycerol or ester or ether thereof, a geranyloxyhexyl group, a hexadecylglycerol, a borneol, a menthol, a 1,3-propanediol, a heptadecyl group, a palmitic acid, a myristic acid, an O3-(oleoyl)lithocholic acid, an O3-(oleoyl)cholenic acid, a dimethoxytrityl, a phenoxazine, a peptide conjugate, an alkylating agent, a phosphate, an amino, a mercapto, a PEG, a MPEG, a [MPEG]2, an alkyl or substituted alkyl, a radiolabeled marker, an enzyme, a hapten, a transport/absorption facilitator, a synthetic ribonuclease, a dinitrophenyl, a HRP, an AP, and a derivative and a combination thereof. 23. A kit comprising an iRNA agent of claim 1, a sterile container in which the iRNA agent is enclosed, and instructions for use.