Angiotensinogen (AGT) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the AGT gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an AGT gene and to methods of preventing and treating an AGT-associated disorder, e.g., high blood pressure.
1 . A double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, for inhibiting expression of angiotensinogen (AGT),
wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand comprises at least 19 contiguous nucleotides from the nucleotide sequence 5′-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666),
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; s is a phosphorothioate linkage; and (Tgn) is a thymidine-glycol nucleic acid (GNA) S-Isomer.
2 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises at least 19 contiguous nucleotides of the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand comprises at least 20 contiguous nucleotides from the nucleotide sequence 5′-usGfsuac (Tgn) cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666).
3 . The dsRNA agent, or a salt thereof, of claim 1 , wherein each strand is independently no more than 30 nucleotides in length.
4 . The dsRNA agent, or a salt thereof, of claim 1 , further comprising a ligand.
5 . The dsRNA agent, or a salt thereof, of claim 4 , wherein;
the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a (a) salt thereof.
6 . The dsRNA agent, or a salt thereof, of claim 5 , wherein the ligand is
7 . The dsRNA agent, or a salt thereof, of claim 6 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
8 . The dsRNA agent, or a salt thereof, of claim 7 , wherein X is O.
9 . The dsRNA agent, or a salt thereof, of claim 1 , wherein the sense strand comprises at least 19 contiguous nucleotides of the nucleotide sequence 5′-gsuscaucCfaCfAfAfugagaguaca-3′ (SEQ ID NO:482) and the antisense strand comprises at least 21 contiguous nucleotides from the nucleotide sequence 5′-usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3′ (SEQ ID NO:666).
10 . An isolated cell containing the dsRNA agent, or a salt thereof, of claim 1 .
11 . A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or a salt thereof, of claim 1 .
12 . A method of inhibiting expression of an AGT gene in a cell, the method comprising contacting the cell with the dsRNA agent, or a salt thereof, of claim 1 , thereby inhibiting expression of the AGT gene in the cell.
13 . The method of claim 12 , wherein:
(a) contacting the cell with the dsRNA agent, or a salt thereof, inhibits the expression of the AGT gene by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%; or
(b) the cell is in a subject, and inhibiting the expression of the AGT gene decreases AGT protein level in serum of the subject by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.
14 . A method of treating an AGT-associated disorder in a subject, comprising administering to the subject the dsRNA agent, or a salt thereof, of claim 1 , thereby treating the AGT-associated disorder in the subject.
15 . The method of claim 14 , wherein:
(a) the subject has a systolic blood pressure of at least 130 mm Hg and a diastolic blood pressure of at least 80 mm Hg;
(b) the subject has a systolic blood pressure of at least 140 mm Hg and a diastolic blood pressure of at least 80 mm Hg;
(c) the subject is part of a group susceptible to salt sensitivity, is overweight, is obese, or is pregnant; or
(d) the subject is human.
16 . The method of claim 14 , wherein the dsRNA agent, or a salt thereof, is administered to the subject subcutaneously.
17 . The method of claim 14 , further comprising administering to the subject an additional therapeutic agent for treatment of hypertension.
18 . The method of claim 14 , wherein the AGT-associated disorder is selected from the group consisting of high blood pressure, hypertension, borderline hypertension, primary hypertension, secondary hypertension isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, labile hypertension; hypertensive heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vasculopathy, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiac myopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurism, ventricular fibrosis, heart failure, myocardial infarction, angina, stroke, chronic kidney disease, renal disease, renal failure, systemic sclerosis, intrauterine growth restriction (IUGR), fetal growth restriction, obesity, liver steatosis/fatty liver, non-alcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), glucose intolerance, type 2 diabetes (non-insulin dependent diabetes), and metabolic syndrome.
19 . The dsRNA agent, or a salt thereof, of claim 4 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
20 . The dsRNA agent, or a salt thereof, of claim 4 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
21 . The dsRNA agent, or a salt thereof, of claim 2 , wherein each strand is independently no more than 30 nucleotides in length.
22 . The dsRNA agent, or a salt thereof, of claim 2 , further comprising a ligand.
23 . The dsRNA agent, or a salt thereof, of claim 22 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof.
24 . The dsRNA agent, or a salt thereof, of claim 22 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
25 . The dsRNA agent, or a salt thereof, of claim 22 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
26 . The dsRNA agent, or a salt thereof, of claim 23 , wherein the ligand is
27 . The dsRNA agent, or a salt thereof, of claim 26 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
28 . The dsRNA agent, or a salt thereof, of claim 27 , wherein X is O.
29 . The dsRNA agent, or a salt thereof, of claim 9 , wherein each strand is independently no more than 30 nucleotides in length.
30 . The dsRNA agent, or a salt thereof, of claim 9 , further comprising a ligand.
31 . The dsRNA agent, or a salt thereof, of claim 30 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof.
32 . The dsRNA agent, or a salt thereof, of claim 30 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
33 . The dsRNA agent, or a salt thereof, of claim 30 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
34 . The dsRNA agent, or a salt thereof, of claim 31 , wherein the ligand is
35 . The dsRNA agent, or a salt thereof, of claim 34 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
36 . The dsRNA agent, or a salt thereof, of claim 35 , wherein X is O.