KETOHEXOKINASE (KHK) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

A method of treating a subject having a ketohexokinase (KHK)-associated disorder, comprising subcutaneously administering to the subject a therapeutically effective amount of a double stranded RNAi agent,

• wherein said double stranded RNAi agent is selected from the group consisting of
• (a) a double stranded RNAi agent for inhibiting expression of a ketohexokinase (KHK) gene, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein said 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 said antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2;
• (b) a double stranded RNAi agent for inhibiting expression of a ketohexokinase (KHK) gene, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, the antisense strand comprising a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense sequences listed in any one of Tables 3, 4, 5, 6, and 7;
• (c) a double stranded RNAi agent for inhibiting expression of a ketohexokinase (KHK) gene, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein said 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 said 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 said sense strand and substantially all of the nucleotides of said antisense strand are modified nucleotides, and
• wherein said sense strand is conjugated to a ligand attached at the 3′-terminus;
• (d) a double stranded RNAi agent capable of inhibiting the expression of a ketohexokinase (KHK) gene, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region, wherein said antisense strand comprises a region complementary to part of an mRNA encoding KHK, wherein each strand is about 14 to about 30 nucleotides in length, wherein said double stranded RNAi agent is represented by formula (III):
• sense:
• 5′np-Na—(XXX)i—Nb—YYY—Nb—(ZZZ)j—Na-nq 3′
• antisense:
• 3′np′—Na′—(X′X′X′)k—Nb′—Y′Y′Y′—Nb′—(Z′Z′Z′)l—Na′-nq′5′ (III)
• wherein:
• i, j, k, and l 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;
• and
• (e) a double stranded RNAi agent for inhibiting expression of a ketohexokinase (KHK), gene
• wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
• wherein said 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 said 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 said sense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
• wherein said sense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus,
• wherein substantially all of the nucleotides of said antisense strand comprise a modification selected from the group consisting of a 2′-O-methyl modification and a 2′-fluoro modification,
• wherein said antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and
• wherein said sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.