Compositions and methods for inhibition of HAO1 (Hydroxyacid Oxidase 1 (Glycolate Oxidase)) gene expression

1. A double stranded RNAi agent capable of inhibiting expression of HAO1 in a cell, wherein said double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand nucleotide sequence consists of SEQ ID NO:589 and the antisense strand nucleotide sequence consists of SEQ ID NO:706;

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.

2. The double stranded RNAi agent of claim 1 , wherein all of the nucleotides of said sense strand and all of the nucleotides of said antisense strand are modified nucleotides.

3. The double stranded RNAi agent of claim 1 , wherein at least one of said modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a nucleotide comprising a 5′ phosphate or 5′ phosphate mimic, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.

4. The double stranded RNAi agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

5. The double stranded RNAi agent claim 1 , wherein the ligand is

6. The double stranded RNAi agent of claim 1 , wherein the ligand is attached to the 3′ end of the sense strand.

7. The double stranded RNAi agent of claim 6 , wherein the RNAi agent is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

8. The double stranded RNAi agent of claim 1 , wherein said agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

9. The double stranded RNAi agent of claim 8 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand.

10. The double stranded RNAi agent of claim 8 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of one strand.

11. The double stranded RNAi agent of claim 8 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the both the 5′- and 3′-terminus of one strand.

12. The double stranded RNAi agent of claim 1 , wherein the base pair at the 1 position of the 5′-end of the antisense strand of the duplex is an AU base pair.

13. The double stranded RNAi agent of claim 1 , wherein the sense strand nucleotide sequence comprises SEQ ID NO:589 and the antisense strand nucleotide sequence comprises SEQ ID NO:706.

14. The double stranded RNAi agent of claim 1 , wherein the sense strand nucleotide sequence consists of SEQ ID NO:589 and the antisense strand nucleotide sequence consists of SEQ ID NO:706.

15. A vector containing the double stranded RNAi agent of claim 1 .

16. A cell containing the double stranded RNAi agent of claim 1 .

17. A pharmaceutical composition comprising the double stranded RNAi agent of claim 1 .

18. A method of inhibiting HAO1 expression in a cell, the method comprising:

(a) contacting the cell with the double stranded RNAi agent of claim 1 ; and

(b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a HAO1 gene, thereby inhibiting expression of the HAO1 gene in the cell.

19. The double stranded RNAi agent of claim 1 , wherein the sense strand consists of SEQ ID NO:213 (gsascuuuCfaUfCfCfuggaaauauaL96) and the antisense strand consists of SEQ ID NO:330 (usAfsuauUfuCfCfaggaUfgAfaagucscsa) and each abbreviation represents a nucleotide monomer as follows:

Abbreviation

Nucleotide(s)

Af

2′-fluoroadenosine-3′-phosphate

Afs

2′-fluoroadenosine-3′-phosphorothioate

Cf

2′-fluorocytidine-3′-phosphate

U

Uridine-3′-phosphate

Uf

2′-fluorouridine-3′-phosphate

a

2′-O-methyladenosine-3′-phosphate

as

2′-O-methyladenosine-3′-phosphorothioate

c

2′-O-methylcytidine-3′-phosphate

cs

2′-O-methylcytidine-3′-phosphorothioate

g

2′-O-methylguanosine-3′-phosphate

gs

2′-O-methylguanosine-3′-phosphorothioate

u

2′-O-methyluridine-3′-phosphate

us

2′-O-methyluridine-3′-phosphorothioate

s

phosphorothioate linkage

L96

N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-

hydroxyprolinol Hyp-(GalNAc-alkyl)3.