Compositions and methods for inhibiting expression of transthyretin

A pharmaceutical composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of transthyretin (TTR), wherein the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand is 19, 20, 21, 22, 23, or 24 nucleotides in length and comprises AUGGAAUACUCUUGGUUACNN (SEQ ID NO:450) and the sense strand of the dsRNA is 19, 20, 21, 22, 23, or 24 nucleotides in length, and comprises a region complementary to the antisense strand, wherein the dsRNA comprises at least one chemically modified nucleotide and wherein the pharmaceutical composition has an ED50 in humans of less than 0.03 mg dsRNA/kg.

A pharmaceutical composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of transthyretin (TTR), wherein the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises AUGGAAUACUCUUGGUUACNN (SEQ ID NO:450) and the sense strand of the dsRNA is 19, 20, 21, 22, 23, or 24 nucleotides in length, and comprises a region complementary to the antisense strand, wherein the dsRNA comprises at least one chemically modified nucleotide and wherein the pharmaceutical composition reduces human serum TTR protein by at least 50%, as compared prior to treatment, at a dose of less than 0.03 mg dsRNA/kg.

A pharmaceutical composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of transthyretin (TTR), wherein the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand comprises AUGGAAUACUCUUGGUUACNN (SEQ ID NO:450) and the sense strand of the dsRNA is 19, 20, 21, 22, 23, or 24 nucleotides in length, wherein the dsRNA comprises at least one chemically modified nucleotide and wherein the pharmaceutical composition reduces human serum TTR protein by at least 70%, as compared to prior to treatment, at a dose of 0.3 mg dsRNA/kg.

A method of treating a subject with hereditary transthyretin mediated amyloidosis comprising administering via intravenous infusion to a human in need of such treatment 0.3 mg dsRNA/kg every three weeks, wherein the dsRNA comprises a sense strand and an antisense strand, the sense strand consisting of the nucleotide sequence GuAAccAAGAGuAuuccAudTdT (SEQ ID NO:

• 1009) and the antisense strand consisting of the nucleotide sequence AUGGAAuACUCUUGGUuACdTdT (SEQ ID NO:
• 1010), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, a is 2′-O-methyladenosine, c is 2′-O-methylcytidine, g is 2′-O-methylguanosine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine, and wherein the dsRNA is in a lipid nanoparticle formulation comprising MC3/DSPC/cholesterol/PEG-DMG at a ratio of about 50/10/38.5/1.5 mol %.

A pharmaceutical composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of transthyretin (TTR), wherein the dsRNA comprises a sense strand and an antisense strand, wherein the antisense strand consists of the nucleotide sequence AUGGAAuACUCUUGGUuACdTdT (SEQ ID NO:1010), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, a is 2′-O-methyladenosine, c is 2′-O-methylcytidine, g is 2′-O-methylguanosine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine, and the sense strand consists of GuAAccAAGAGuAuuccAudTdT (SEQ ID NO:

• 1009), wherein A is adenosine, C is cytidine, G is guanosine, U is uridine, a is 2′-O-methyladenosine, c is 2′-O-methylcytidine, g is 2′-O-methylguanosine, u is 2′-O-methyluridine and dT is 2′-deoxythymidine.