Methods and compositions for the specific inhibition of glycolate oxidase (hao1) by double-stranded rna

Patent metadata

Field	Value
Publication number	US-2018291379-A1
Application number	US-201715793441-A
Country	US
Kind code	A1
Filing date	Oct 25, 2017
Priority date	Dec 27, 2013
Publication date	Oct 11, 2018
Grant date	—

Abstract

This invention relates to compounds, compositions, and methods useful for reducing Glycolate Oxidase (HAO1) target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

First claim

1 - 85 . (canceled)

86 . A method of treating a subject having primary hyperoxaluria 1 (PH1), the method comprising administering to the subject an effective amount of a double stranded nucleic acid that comprises a first oligonucleotide strand and a second oligonucleotide strand that form a duplex region, wherein the second oligonucleotide strand is sufficiently complementary to a target HAO1 mRNA along at least 15 nucleotides of the oligonucleotide strand length to reduce expression of the HAO1 target mRNA.

87 . The method of claim 86 , wherein administration of the double stranded nucleic acid to the subject inhibits oxalate accumulation in the subject.

88 . The method of claim 86 , wherein administration of the nucleic acid to the subject results in an increase in a glycolate/creatinine ratio in urine of the subject and a decrease in a oxalate/creatinine ratio in urine of the subject.

89 . The method of claim 86 , wherein administration of the nucleic acid to the subject inhibits accumulation of calcium precipitates in a kidney of the subject.

90 . The method of claim 86 , wherein administration of the nucleic acid to the subject is performed subcutaneously.

91 . The method of claim 86 , wherein administration of the double stranded nucleic acid to the subject results in at least a 50% reduction of HAO1 mRNA levels in the subject.

92 . The method of claim 86 , wherein administration of the double stranded nucleic acid to the subject results in at least an 80-90% reduction of HAO1 mRNA levels in the subject.

93 . The method of claim 86 , wherein the subject is a human subject.

94 . The method of claim 93 , wherein the subject is a pediatric human subject.

95 . The method of claim 86 , wherein the subject has an AGT1 mutation that results in accumulation of oxylate.

96 . The method of claim 86 , wherein one or more GalNac moieties are conjugated to one or more nucleotides of the first oligonucleotide strand and/or the second oligonucleotide strand.

97 . The method of claim 86 , wherein one or more GalNac moieties are conjugated to the 3′ terminal nucleotide of the first oligonucleotide strand.

98 . The method of claim 86 , wherein the first oligonucleotide strand is 15-66 nucleotides in length and the second oligonucleotide strand is 19-66 nucleotides in length.

99 . The method of claim 86 , wherein the first oligonucleotide strand is 21 nucleotides in length and the second oligonucleotide strand is 23 nucleotides in length.

100 . The method of claim 99 , wherein the second oligonucleotide strand forms a 3′-overhang of 2 nucleotides in length.

101 . The method of claim 86 , wherein the first oligonucleotide strand and/or the second oligonucleotide strand comprises one or more modified nucleotides.

102 . The method of claim 101 , wherein each of the one or more modified nucleotides is independently a 2′-O-methyl modified nucleotide or a 2′-fluoro modified nucleotide.

103 . The method of claim 102 , wherein the first oligonucleotide strand comprises a 3′ region that extends beyond the duplex region formed with the second oligonucleotide strand and that comprises a tetraloop structure

104 . A method of reducing or preventing kidney damage in a subject having primary hyperoxaluria 1 (PH1), the method comprising administering to the subject an effective amount of a double stranded nucleic acid that comprises a first oligonucleotide strand and a second oligonucleotide strand that form a duplex region, wherein the second oligonucleotide strand is sufficiently complementary to a target HAO1 mRNA along at least 15 nucleotides of the oligonucleotide strand length to reduce expression of the HAO1 target mRNA by RNA interference, wherein the first oligonucleotide strand and/or the second oligonucleotide strand comprise one or more modified nucleotides independently selected from 2′-O-methyl modified nucleotides and 2′-fluoro modified nucleotides, and wherein one or more GalNac moieties are conjugated to one or more nucleotides of the first oligonucleotide strand and/or the second oligonucleotide strand.

105 . The method of claim 104 , wherein the first oligonucleotide strand is 21 nucleotides in length and the second oligonucleotide strand is 23 nucleotides in length, and wherein the second oligonucleotide strand forms a 3′-overhang of 2 nucleotides in length.

Assignees

• Dicerna Pharmaceuticals Inc

Inventors

• Brown Bob D
• Dudek Henryk T

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• C12Y101/03015

  (S)-2-Hydroxy-acid oxidase (1.1.3.15) · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N15/1137 Primary

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title