Compositions and methods for inhibition of HAO1 (hydroxyacid oxidase 1 (glycolate oxidase)) gene expression
The invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the HAO1 gene, and methods of using such RNAi agents to inhibit expression of HAO1 and methods of treating subjects having, e.g., PH1.
1. A double stranded RNAi agent, or salt thereof, that inhibits expression of HAO1 in a cell,
comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-gsascuuuCfaUfCfCfuggaaauauaL96-3′ (SEQ ID NO:213) and the antisense strand comprises the nucleotide sequence 5′-usAfsuauUfuCfCfaggaUfgAfaagucscsa-3′ (SEQ ID NO:330),
wherein a, g, c, and u are 2′-O-methyl (2′-OMe) modified A, G, C, and U nucleotides, respectively; Af, Gf, Cf, and Uf are 2′ fluoro A, G, C, and U modified nucleotides, respectively; s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.
2. A pharmaceutical composition comprising the double stranded RNAi agent of claim 1 .
3. An isolated cell containing the double stranded RNAi agent of claim 1 .
4. A double stranded RNAi agent, or salt thereof, that inhibits expression of HAO1 in a cell,
comprising a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence of 5′-gsascuuuCfaUfCfCfuggaaauaua-3′ (SEQ ID NO:213) and the antisense strand comprises the nucleotide sequence 5′-usAfsuauUfuCfCfaggaUfgAfaagucscsa-3′ (SEQ ID NO:330),
wherein a, g, c, and u are 2′-O-methyl (2′-OMe) modified A, G, C, and U nucleotides, respectively; Af, Gf, Cf, and Uf are 2′ fluoro A, G, C, and U modified nucleotides, respectively; and s is a phosphorothioate linkage,
wherein a ligand is conjugated to the 3′ end of the sense strand as shown in the following schematic
wherein X is O.
5. A pharmaceutical composition comprising the double stranded RNAi agent of claim 4 .
6. An isolated cell containing the double stranded RNAi agent of claim 4 .
7. The pharmaceutical composition of claim 2 , wherein the double stranded RNAi agent is present in an unbuffered solution.
8. The pharmaceutical composition of claim 7 , wherein the unbuffered solution is water.
9. The pharmaceutical composition of claim 6 , wherein the unbuffered solution is saline.
10. The pharmaceutical composition of claim 2 , wherein the double stranded RNAi agent is present in a buffer solution.
11. The pharmaceutical composition of claim 10 wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
12. The pharmaceutical composition of claim 5 , wherein the double stranded RNAi agent is present in an unbuffered solution.
13. The pharmaceutical composition of claim 12 , wherein the unbuffered solution is water.
14. The pharmaceutical composition of claim 12 , wherein the unbuffered solution is saline.
15. The pharmaceutical composition of claim 5 , wherein the double stranded RNAi agent is present in a buffer solution.
16. The pharmaceutical composition of claim 15 wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.