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NZ770717B2 - Angiotensinogen (agt) irna compositions and methods of use thereof - Google Patents
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NZ770717B2 - Angiotensinogen (agt) irna compositions and methods of use thereof - Google Patents

Angiotensinogen (agt) irna compositions and methods of use thereof

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Publication number
NZ770717B2
NZ770717B2 NZ770717A NZ77071719A NZ770717B2 NZ 770717 B2 NZ770717 B2 NZ 770717B2 NZ 770717 A NZ770717 A NZ 770717A NZ 77071719 A NZ77071719 A NZ 77071719A NZ 770717 B2 NZ770717 B2 NZ 770717B2
Authority
NZ
New Zealand
Prior art keywords
hypertension
pharmaceutically acceptable
acceptable salt
dsrna agent
agent
Prior art date
Application number
NZ770717A
Other versions
NZ770717A (en
Inventor
Donald Foster
Gregory Hinkle
Mark K Schlegel
Original Assignee
Alnylam Pharmaceuticals Inc
Filing date
Publication date
Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Priority claimed from PCT/US2019/032150 external-priority patent/WO2019222166A1/en
Publication of NZ770717A publication Critical patent/NZ770717A/en
Publication of NZ770717B2 publication Critical patent/NZ770717B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1136—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against growth factors, growth regulators, cytokines, lymphokines or hormones
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/312—Phosphonates
    • C12N2310/3125—Methylphosphonates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/343—Spatial arrangement of the modifications having patterns, e.g. ==--==--==--
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate

Abstract

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.

Claims (43)

We claim:
1. A double stranded ribonucleic acid (dsRNA) agent, or a pharmaceutically acceptable salt thereof, for inhibiting expression of angiotensinogen (AGT) in a cell, 5 wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, ses a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5’- gsuscaucCfaCfAfAfugagaguaca-3’ (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ (SEQ ID NO:666), 10 wherein a, g, c, and u are 2'-O-methyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are oro A, G, C and U, respectively; s is a phosphorothioate e; and (Tgn) is a thymidine-glycol nucleic acid (GNA) S-Isomer.
2. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1, further comprising a ligand. 15
3. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 2, wherein the ligand is conjugated to the 3’ end of the sense strand of the dsRNA agent, or salt thereof.
4. The dsRNA agent, or a pharmaceutically able salt thereof, of claim 2 or 3, wherein the ligand is an ylgalactosamine (GalNAc) derivative. 20
5. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 4, n the ligand is HO OH O H H HO O N N O HO OH O H H HO O N N O O O O HO OH HO O N N O AcHN H H O . 21572758_1 (GHMatters) P114838.NZ
6. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 5, wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic O P X HO OH O H H O HO O N N O AcHN O HO OH O H H H HO O N N O N AcHN O O O O HO OH HO O N N O AcHN H H and, wherein X is O or S. 5
7. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 6, wherein the X is O.
8. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 2, wherein the ligand is one or more GalNAc derivatives attached through a lent, bivalent, or trivalent branched linker. 10 9. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the sense strand ses the tide sequence 5’- gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO:482 and the antisense strand comprises the nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO:666, wherein a, g, c, and u are ethyl (2'-OMe) A, G, C, and U, respectively; Af, Gf, 15 Cf and Uf are 2'-fluoro A, G, C and U, respectively; s is a phosphorothioate linkage; and
9. (Tgn) is a thymidine-glycol nucleic acid (GNA) er; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic 21572758_1 (GHMatters) P114838.NZ wherein X is O.
10. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 9, 5 which is in salt form.
11. The dsRNA agent, or a pharmaceutically able salt thereof, of claim 1, wherein the sense strand consists of the nucleotide sequence 5’- gsuscaucCfaCfAfAfugagaguaca-3’ of SEQ ID NO:482 and the antisense strand consists of the nucleotide sequence 5’- usGfsuac(Tgn)cucauugUfgGfaugacsgsa-3’ of SEQ ID NO:666, 10 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 orothioate linkage; and (Tgn) is a ine-glycol nucleic acid (GNA) S-Isomer; and wherein the 3’-end of the sense strand is conjugated to a ligand as shown in the following schematic 21572758_1 (GHMatters) P114838.NZ n X is O.
12. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 11, which is in a salt form. 5
13. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12.
14. A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1-8. 10
15. A pharmaceutical composition for inhibiting expression of a gene encoding AGT comprising the dsRNA agent, or a pharmaceutically able salt thereof, of claim 9 or 10 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition for inhibiting expression of a gene ng AGT comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 11 15 or 12 and a pharmaceutically acceptable carrier.
17. An in vitro method of inhibiting expression of an AGT gene in a cell, the method sing contacting the cell with the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12 or the ceutical composition of any one of claims 14-16, thereby inhibiting expression of the AGT gene in the cell. 20
18. The method of claim 17, wherein contacting the cell with the dsRNA agent, or a ceutically acceptable salt thereof, inhibits the expression of AGT is by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.
19. A pharmaceutical composition for treating an AGT-associated disease in a subject, comprising the dsRNA agent, or a pharmaceutically acceptable salt f, of any 25 one of claims 1-12 or the pharmaceutical composition of any one of claims 14-16.
20. The pharmaceutical composition of claim 19, wherein the AGT–associated disease is selected from the group consisting of high blood pressure, hypertension, borderline hypertension, primary hypertension, secondary hypertension isolated ic or diastolic hypertension, pregnancy-associated hypertension, diabetic ension, resistant 58_1 (GHMatters) P114838.NZ hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, ary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, labile hypertension; 5 hypertensive heart disease, hypertensive nephropathy, sclerosis, arteriosclerosis, vasculopathy, diabetic nephropathy, diabetic retinopathy, chronic heart e, cardiomyopathy, diabetic cardiac myopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurism, ventricular fibrosis, heart failure, myocardial infarction, angina, stroke, renal disease, chronic kidney disease, renal failure, systemic sclerosis, intrauterine growth 10 restriction (IUGR) , fetal growth restriction, obesity, liver sis/ fatty liver, non-alcoholic Steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD); glucose intolerance, type 2 diabetes (non-insulin ent diabetes), and metabolic me.
21. The pharmaceutical composition of claim 19, wherein the subject has a systolic blood pressure of at least 130 mm Hg and a diastolic blood pressure of at least 80 15 mm Hg.
22. The ceutical ition of claim 19, n the subject has a systolic blood pressure of at least 140 mm Hg and a diastolic blood pressure of at least 80 mm Hg.
23. The pharmaceutical ition of claim 19, wherein the subject is human. 20
24. The pharmaceutical composition of claim 19, wherein the subject is part of a group susceptible to salt sensitivity, is overweight, is obese, or is pregnant.
25. The pharmaceutical composition of claim 19, wherein the dsRNA agent, or a pharmaceutically able salt f, is to be administered at a dose of about 0.01 mg/kg to about 50 mg/kg. 25
26. The pharmaceutical composition of claim 19, wherein the dsRNA agent, or a pharmaceutically acceptable salt f, is to be administered subcutaneously.
27. The pharmaceutical composition of claim 19, which is to be administered in combination with an additional therapeutic agent for treatment of hypertension.
28. The pharmaceutical composition of claim 27, wherein the additional 30 therapeutic agent is selected from the group consisting of a diuretic, an angiotensin 21572758_1 (GHMatters) P114838.NZ converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a beta-blocker, a vasodialator, a calcium channel blocker, an aldosterone antagonist, an alpha2-agonist, a renin inhibitor, an alpha-blocker, a peripheral acting adrenergic agent, a selective D1 receptor partial agonist, a nonselective alpha-adrenergic antagonist, a steroidal antimineralocorticoid 5 agent, an angiotensin receptor-neprilysin inhibitors (ARNi), sacubitril/valsartan; or an endothelin receptor antagonist (ERA), sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, bosentan, macitentan, and tezosentan; a ation of any of the foregoing; and a hypertension therapeutic agent ated as a combination of agents.
29. The pharmaceutical composition of claim 28, wherein the additional 10 therapeutic agent comprises an angiotensin II or antagonist.
30. The ceutical composition of claim 29, wherein the angiotensin II or antagonist is selected from the group consisting of losartan, tan, olmesartan, eprosartan, and rtan.
31. A kit comprising the dsRNA agent, or a pharmaceutically acceptable salt 15 thereof, of any one of claims 1-12 or the pharmaceutical composition of any one of claims 14-16.
32. Use of the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12, or the pharmaceutical composition of any one of claims 14-16, in the manufacture of a medicament for inhibiting expression of an AGT gene in a cell. 20
33. Use of the dsRNA agent, or a pharmaceutically acceptable salt thereof, of any one of claims 1-12, or the ceutical composition of any one of claims 14-16, in the manufacture of a medicament for treating an AGT-associated disease in a subject in need thereof.
34. The use of claim 33, wherein the AGT–associated disease is selected from the group 25 consisting of high blood pressure, hypertension, line hypertension, primary hypertension, secondary hypertension isolated systolic or diastolic hypertension, pregnancyassociated hypertension, ic hypertension, ant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular 30 ension, glaucoma, pulmonary hypertension, portal hypertension, ic venous hypertension, systolic hypertension, labile hypertension; ensive heart disease, 21572758_1 (GHMatters) P114838.NZ 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, renal disease, chronic kidney disease, 5 renal failure, systemic sclerosis, intrauterine growth restriction (IUGR) , fetal growth restriction, obesity, liver steatosis/ fatty liver, non-alcoholic Steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD); glucose intolerance, type 2 diabetes (non-insulin dependent diabetes), and metabolic syndrome.
35. The use of claim 33, n the t has a ic blood pressure of at least 130 10 mm Hg and a diastolic blood re of at least 80 mm Hg.
36. The use of claim 33, wherein the subject has a systolic blood pressure of at least 140 mm Hg and a diastolic blood pressure of at least 80 mm Hg.
37. The use of claim 33, wherein the subject is part of a group susceptible to salt sensitivity, is overweight, is obese, or is nt. 15
38. The use of claim 33, wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is to be administered at a dose of about 0.01 mg/kg to about 50 mg/kg.
39. The use of claim 33, wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is to be administered subcutaneously.
40. The use of claim 33, which is to be administered in combination with an additional 20 eutic agent for treatment of hypertension.
41. The use of claim 40, wherein the additional therapeutic agent is selected from the group ting of a diuretic, an ensin converting enzyme (ACE) inhibitor, an ensin II receptor nist, a locker, a vasodialator, a calcium channel blocker, an aldosterone antagonist, an alpha2-agonist, a renin inhibitor, an alpha-blocker, a peripheral 25 acting adrenergic agent, a selective D1 or partial agonist, a nonselective alphaadrenergic antagonist, a steroidal antimineralocorticoid agent, an angiotensin receptorneprilysin tors (ARNi), sacubitril/valsartan; or an endothelin receptor antagonist (ERA), sitaxentan, ambrisentan, ntan, BQ-123, zibotentan, bosentan, macitentan, and tezosentan; a combination of any of the foregoing; and a hypertension therapeutic agent 30 formulated as a combination of agents. 21572758_1 (GHMatters) P114838.NZ
42. The use of claim 41, wherein the additional therapeutic agent comprises an angiotensin II receptor nist.
43. The use of claim 42, wherein the angiotensin II receptor antagonist is selected from the group consisting of losartan, tan, olmesartan, eprosartan, and azilsartan. 21572758_1 (GHMatters) P114838.NZ 3%ng 333 333 Egg Egg Egg magma: mmmm?? mammng gammy? :Ea i: i? ..... ..... Ema am mam 30%me mmmcwm ?g «W: 9 GE om“: mom: CL) {luawmnmd :0 %) m: @me @me 3%? mg g @ meEmd 9me mxxmgm Rmmmagzés E?mag mmmmmgg wwwmwn?? Ewmmsg gwmmsg Lg. L : .......... . LL wwwmmsmq wm?wia?c em mmo?awmonm mw acmmmggam a ,wl GE a8 (Luammmw 3.0 %) Lav Aim E? 3me $me g memmig % Ea. wmwmwam? mmmwwam? mamwa? mmcmawmmm E “mmgmm mxmmm 9‘ mowtmm?am GE {luawmewd £0 %> mv -% gydmdag <22 <1) g «<3- . 2 iii ggdmdmmaugsgm‘ E k .. .. .. vmggs sgm \\\\\\
NZ770717A 2019-05-14 Angiotensinogen (agt) irna compositions and methods of use thereof NZ770717B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862671094P 2018-05-14 2018-05-14
US201862727141P 2018-09-05 2018-09-05
US201962816996P 2019-03-12 2019-03-12
PCT/US2019/032150 WO2019222166A1 (en) 2018-05-14 2019-05-14 Angiotensinogen (agt) irna compositions and methods of use thereof

Publications (2)

Publication Number Publication Date
NZ770717A NZ770717A (en) 2025-06-27
NZ770717B2 true NZ770717B2 (en) 2025-09-30

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