iRNA Compositions and Methods for Silencing MYLIP

A double stranded RNA (dsRNA) agent for inhibiting expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the double stranded RNA agent comprises a sense strand and an antisense strand forming a double stranded region,

• wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
• 1, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
• 2,
• wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and
• wherein the sense strand is conjugated to a ligand attached at the 3′-terminus.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein said dsRNA agent comprises a sense strand complementary to an antisense strand, wherein said antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein said dsRNA agent is represented by formula (Ii):

• (Ii)
• sense:
• 5′ np-Na-(X X X)i-Nb-Y Y Y-Nb-(Z Z Z)j-Na-nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-
• Na′-nq′ 5′
• wherein:
• i, j, k, and 1 are each independently 0 or 1;
• p, p′, q, and q′ are each independently 0-6;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• each Nb and Nb′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;
• each np, np′, nq, and nq′, each of which may or may not be present, independently represents an overhang nucleotide;
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides;
• modifications on Nb differ from the modification on Y and modifications on Nb′ differ from the modification on Y′;
• and
• wherein the sense strand is conjugated to at least one ligand.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein the dsRNA agent is represented by formula (Ii):

• (Ii)
• sense:
• 5′ np-Na-(X X X)i-Nb-Y Y Y-Nb-(Z Z Z)j-Na-nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-
• Na′-nq′ 5′
• wherein:
• i, j, k, and 1 are each independently 0 or 1;
• p, p′, q, and q′ are each independently 0-6;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• each Nb and Nb′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;
• each np, np′, nq, and nq′, each of which may or may not be present independently represents an overhang nucleotide;
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides, and wherein the modifications are 2′-O-methyl or 2′-fluoro modifications;
• modifications on Nb differ from the modification on Y and modifications on Nb′ differ from the modification on Y′;
• and
• wherein the sense strand is conjugated to at least one ligand.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein the dsRNA agent is represented by formula (Ii):

• (Ii)
• sense:
• 5′ np-Na-(X X X)i-Nb-Y Y Y-Nb-(Z Z Z)j-Na-nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-
• Na′-nq′ 5′
• wherein:
• i, j, k, and 1 are each independently 0 or 1;
• each np, nq, and nq′, each of which may or may not be present, independently represents an overhang nucleotide;
• p, q, and q′ are each independently 0-6;
• np′>0 and at least one np′ is linked to a neighboring nucleotide via a phosphorothioate linkage;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• each Nb and Nb′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides, and wherein the modifications are 2′-O-methyl or 2′-fluoro modifications;
• modifications on Nb differ from the modification on Y and modifications on Nb′ differ from the modification on Y′;
• and
• wherein the sense strand is conjugated to at least one ligand.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein the dsRNA agent is represented by formula (Ii):

• (Ii)
• sense:
• 5′ np-Na-(X X X)i-Nb-Y Y Y-Nb-(Z Z Z)j-Na-nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-
• Na′-nq′ 5′
• wherein:
• i, j, k, and 1 are each independently 0 or 1;
• each np, nq, and nq′, each of which may or may not be present, independently represents an overhang nucleotide;
• p, q, and q′ are each independently 0-6;
• np′>0 and at least one np′ is linked to a neighboring nucleotide via a phosphorothioate linkage;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• each Nb and Nb′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides, and wherein the modifications are 2′-O-methyl or 2′-fluoro modifications;
• modifications on Nb differ from the modification on Y and modifications on Nb′ differ from the modification on Y′;
• and
• wherein the sense strand is conjugated to at least one ligand, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein the dsRNA agent is represented by formula (Ii):

• (Ii)
• sense:
• 5′ np-Na-(X X X)i-Nb-Y Y Y-Nb-(Z Z Z)j-Na-nq 3′
• antisense:
• 3′ np′-Na′-(X′X′X′)k-Nb′-Y′Y′Y′-Nb′-(Z′Z′Z′)l-
• Na′-nq′ 5′
• wherein:
• i, j, k, and 1 are each independently 0 or 1;
• each np, nq, and nq′, each of which may or may not be present, independently represents an overhang nucleotide;
• p, q, and q′ are each independently 0-6;
• np′>0 and at least one np′ is linked to a neighboring nucleotide via a phosphorothioate linkage;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• each Nb and Nb′ independently represents an oligonucleotide sequence comprising 0-10 nucleotides which are either modified or unmodified or combinations thereof;
• XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides, and wherein the modifications are 2′-O-methyl or 2′-fluoro modifications;
• modifications on Nb differ from the modification on Y and modifications on Nb′ differ from the modification on Y′;
• wherein the sense strand comprises at least one phosphorothioate linkage;
• and
• wherein the sense strand is conjugated to at least one ligand, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to part of an mRNA encoding MYLIP, wherein each strand is about 14 to about 30 nucleotides in length, wherein the dsRNA agent is represented by formula (Ij):

• sense:
• (Ij)
• 5′ np-Na-Y Y Y-Na-nq 3′
• antisense:
• 3′ np′-Na′-Y′Y′Y′-Na′-nq′ 5′
• wherein:
• each np, nq, and nq′, each of which may or may not be present, independently represents an overhang nucleotide;
• p, q, and q′ are each independently 0-6;
• np′>0 and at least one np′ is linked to a neighboring nucleotide via a phosphorothioate linkage;
• each Na and Na′ independently represents an oligonucleotide sequence comprising 0-25 nucleotides which are either modified or unmodified or combinations thereof, each sequence comprising at least two differently modified nucleotides;
• YYY and Y′Y′Y′ each independently represent one motif of three identical modifications on three consecutive nucleotides, and wherein the modifications are 2′-O-methyl or 2′-fluoro modifications;
• wherein the sense strand comprises at least one phosphorothioate linkage;
• and
• wherein the sense strand is conjugated to at least one ligand, wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.

A double stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of myosin regulatory light chain interacting protein (MYLIP) in a cell, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,

• wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
• 1, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
• 2,
• wherein substantially all of the nucleotides of the sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
• wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
• wherein substantially all of the nucleotides of the antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
• wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
• wherein the sense strand is conjugated to one or more GalNAc derivatives attached through a monovalent, bivalent or trivalent branched linker at the 3′-terminus.