Methods and compositions for inhibition of hao1 (hydroxyacid oxidase 1 (glycolate oxidase)) gene expression

A method for treating a human subject having primary hyperoxaluria type I (PH1), the method comprising

• administering to the subject a double stranded RNAi agent that inhibits expression of HAO1, or salt thereof, wherein treating the subject comprises reducing plasma oxalate levels in the subject,
• wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
• wherein the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-gsascuuuCfaUfCfCfuggaaauaua-3′ (SEQ ID NO:14) and the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-usAfsuauUfuCfCfaggaUfgAfaagucscsa-3′ (SEQ ID NO:15),
• wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively;
• Af, Gf, Cf, and Uf are 2′-fluoro A, G, C, and U, respectively;
• and s is a phosphorothioate linkage;
• and
• (a) wherein the subject has a body weight of less than about 10 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 4 milligram per kilogram (mg/kg) to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 1 mg/kg to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month beginning one month after a last dose of the loading dose;
• or
• (b) wherein the subject has a body weight of about 10 kg to about 20 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 4 milligram per kilogram (mg/kg) to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 4 mg/kg to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once every three months beginning one month after a last dose of the loading dose, or
• (c) wherein the subject has a body weight of greater than about 20 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 1 milligram per kilogram (mg/kg) to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 1 mg/kg to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once every three months beginning one month after a last dose of the loading dose,
• thereby treating the human subject having PH1.

A method for reducing plasma oxalate in a human subject having primary hyperoxaluria type I (PH1), the method comprising

• administering to the subject a double stranded RNAi agent that inhibits expression of HAO1, or salt thereof,
• wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double stranded region,
• wherein the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-gsascuuuCfaUfCfCfuggaaauaua-3′ (SEQ ID NO:14) and the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-usAfsuauUfuCfCfaggaUfgAfaagucscsa-3′ (SEQ ID NO:15),
• wherein a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively;
• Af, Gf, Cf, and Uf are 2′-fluoro A, G, C, and U, respectively;
• and s is a phosphorothioate linkage, and
• (a) wherein the subject has a body weight of less than about 10 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 4 milligram per kilogram (mg/kg) to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 1 mg/kg to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month beginning one month after a last dose of the loading phase;
• or
• (b) wherein the subject has a body weight of about 10 kg to about 20 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 4 milligram per kilogram (mg/kg) to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 4 mg/kg to about 8 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once every three months beginning one month after a last dose of the loading phase;
• or
• (c) wherein the subject has a body weight of greater than about 20 kilograms (kg),
• wherein the double stranded RNAi agent, or salt thereof, is administered in a dosing regimen comprising a loading phase followed by a maintenance phase, and
• wherein the loading phase comprises administering a dose of about 1 milligram per kilogram (mg/kg) to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once a month for about three months, and the maintenance phase comprises administering a dose of about 1 mg/kg to about 5 mg/kg of the double stranded RNAi agent, or salt thereof, to the subject about once every three months beginning one month after a last dose of the loading phase,
• thereby reducing plasma oxalate in the human subject having PH1.