Dynamic pharmacokinetic-modifying anchors

A method of delivering a compound to the liver of a subject, comprising administering to the subject a compound comprising:

• a first oligonucleotide, wherein the first oligonucleotide comprises 16 to 25 contiguous nucleotides, a 5′ end, a 3′ end, and complementarity to a target gene or target mRNA;
• a second oligonucleotide comprising 12 to 17 contiguous nucleotides, a 5′ end, and a 3′ end, wherein a portion of the 5′ end of the first oligonucleotide is complementary to a portion of the second oligonucleotide, and wherein the second oligonucleotide comprises an N-Acetylgalactosamine (GalNAc) moiety or a derivative thereof conjugated to the 3′ end;
• and
• a pharmacokinetic (PK)-modifying anchor comprising an anchor oligonucleotide comprising a 5′ end, a 3′ end, and at least one polymer conjugated to the 5′ end, wherein the anchor oligonucleotide comprises about 5 to about 15 nucleotides that are complementary to the 3′ end of the first oligonucleotide, and wherein the at least one polymer is at least about 2,000 Da.

A method for treating a disease or a disorder in a patient in need thereof, comprising administering to the patient a compound comprising a first oligonucleotide, a second oligonucleotide, and a pharmacokinetic (PK)-modifying anchor, wherein:

• the first oligonucleotide is between 16 to 25 nucleotides in length, and comprises a 5′ end, a 3′ end, a complementarity to a target gene or target mRNA;
• the second oligonucleotide is between 12 to 17 nucleotides in length, and comprises a 5′ end and a 3′ end;
• and
• the pharmacokinetic (PK)-modifying anchor comprises an anchor oligonucleotide between 5 to 8 nucleotides in length and comprising a 3′ end and a 5′ end, and at least one polymer conjugated to the 5′ end, wherein the at least one polymer is at least about 2,000 Da,
• wherein a portion of the 5′ end of the first oligonucleotide is complementary to the second oligonucleotide and a portion of the 3′ end of the first oligonucleotide is complementary to the anchor oligonucleotide, and
• wherein the second oligonucleotide further comprises conjugate moiety Xc at the 3′ end, at the 5′ end, at an internal position, or a mixture thereof.

A method for treating a disease or a disorder in a patient in need thereof, comprising administering to the patient a compound comprising a first oligonucleotide, a second oligonucleotide, and a pharmacokinetic (PK)-modifying anchor, wherein:

• the first oligonucleotide comprises a 5′ end, a 3′ end, and complementarity to a target gene or target mRNA;
• the second oligonucleotide comprises a 5′ end and a 3′ end;
• and
• the pharmacokinetic (PK)-modifying anchor comprises an anchor oligonucleotide comprising a 3′ end and a 5′ end, and at least one polymer conjugated to the 5′ end, wherein the at least one polymer is at least about 2,000 Da,
• wherein a portion of the 5′ end of the first oligonucleotide is complementary to the second oligonucleotide and a portion of the 3′ end of the first oligonucleotide is complementary to the anchor oligonucleotide, wherein:
• a) the first oligonucleotide is between 21 nucleotides to 25 nucleotides in length;
• b) the second oligonucleotide is between 13 nucleotides and 17 nucleotides in length;
• and
• c) the anchor oligonucleotide is between 5 nucleotides and 8 nucleotides in length;
• a) the first oligonucleotide is 21 nucleotides in length;
• b) the second oligonucleotide is 13 nucleotides in length;
• and
• c) the anchor oligonucleotide is 8 nucleotides in length;
• a) the first oligonucleotide is 23 nucleotides in length;
• b) the second oligonucleotide is 15 nucleotides in length;
• and
• c) the anchor oligonucleotide is 8 nucleotides in length;
• or
• a) the first oligonucleotide is 25 nucleotides in length;
• b) the second oligonucleotide is 17 nucleotides in length;
• and
• c) the anchor oligonucleotide is 8 nucleotides in length.

A method for treating a disease or a disorder in a patient in need thereof, comprising administering to the patient:

• a first oligonucleotide, wherein the first oligonucleotide is 21 nucleotides in length, with a 5′ end and a 3′ end, and is complementary to a target gene or a target mRNA;
• a second oligonucleotide, wherein the second oligonucleotide is 13 nucleotides in length, with a 5′ end and a 3′ end, and is complementary to nucleotides 1-13 of the first oligonucleotide;
• and
• an anchor oligonucleotide, wherein the anchor oligonucleotide is 8 nucleotides in length, with a 5′ end, a 3′ end, and is complementary nucleotides 14-21 of the first oligonucleotide,
• wherein the second oligonucleotide is attached to a molecule comprising a cholesterol, a docosanoic acid, a docosahexaenoic acid, or an N-acetylgalactosamine at the 3′ end,
• wherein the anchor oligonucleotide is attached to a polyethylene glycol polymer comprising a molecular weight of between 10,000 and 40,000 Daltons at the 5′ end,
• wherein the first oligonucleotide comprises complementarity to both the second oligonucleotide and the anchor oligonucleotide to form a duplex, and wherein the 5′ end of the second oligonucleotide is not connected to the 3′ end of the anchor oligonucleotide.

A method for treating a disease or a disorder in a patient in need thereof, comprising administering to the patient:

• an oligonucleotide duplex comprising a first oligonucleotide, wherein the first oligonucleotide is 25 nucleotides in length, with a 5′ end and a 3′ end, and comprises complementarity to a target gene or a target mRNA;
• a second oligonucleotide, wherein the second oligonucleotide is 17 nucleotides in length, with a 5′ end and a 3′ end, is hydrophobically modified, and is complementary to nucleotides 1-17 of the first oligonucleotide;
• and
• an anchor oligonucleotide, wherein the anchor oligonucleotide is 8 nucleotides in length, with a 5′ end and a 3′ end, and is complementarity to nucleotides 18-25 of the first oligonucleotide, wherein the anchor oligonucleotide comprises a pharmacokinetic-modifying moiety.

A method for treating a disease or a disorder in a patient in need thereof, comprising administering to the patient an siRNA duplex comprising:

• a first RNA strand between 21 nucleotides and 25 nucleotides in length and comprising complementarity to a target gene or a target mRNA;
• a second RNA strand between 13 nucleotides and 17 nucleotides in length and having homology with a target sequence;
• and
• an anchor oligonucleotide strand between 5 nucleotides and 8 nucleotides in length, wherein the anchor oligonucleotide strand comprises a polymeric pharmacokinetic-modifying moiety selected from the group consisting of a hydrophilic polycarbonate, a polyethylene glycol (PEG), a block co-polymer, a poloxamer, a polysaccharide, and a poly(lactic-co-glycolic acid) (PLGA),
• wherein the first RNA strand can pair with the second RNA strand to form an asymmetric siRNA, and the anchor oligonucleotide strand binds to a single stranded region of the siRNA.