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NZ727615B2 - Angiotensinogen (agt) irna compositions and methods of use thereof - Google Patents
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NZ727615B2 - Angiotensinogen (agt) irna compositions and methods of use thereof - Google Patents

Angiotensinogen (agt) irna compositions and methods of use thereof Download PDF

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Publication number
NZ727615B2
NZ727615B2 NZ727615A NZ72761515A NZ727615B2 NZ 727615 B2 NZ727615 B2 NZ 727615B2 NZ 727615 A NZ727615 A NZ 727615A NZ 72761515 A NZ72761515 A NZ 72761515A NZ 727615 B2 NZ727615 B2 NZ 727615B2
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New Zealand
Prior art keywords
double
rnai agent
stranded rnai
strand
stranded
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NZ727615A
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NZ727615A (en
Inventor
Brian Bettencourt
Klaus Charisse
Donald Foster
Gregory Hinkle
Satyanarayana Kuchimanchi
Martin Maier
Stuart Milstein
Original Assignee
Alnylam Pharmaceuticals Inc
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Publication date
Application filed by Alnylam Pharmaceuticals Inc filed Critical Alnylam Pharmaceuticals Inc
Priority claimed from PCT/US2015/032099 external-priority patent/WO2015179724A1/en
Publication of NZ727615A publication Critical patent/NZ727615A/en
Publication of NZ727615B2 publication Critical patent/NZ727615B2/en

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Abstract

The present invention relates to RNAi agents, e.g., double- stranded RNAi agents, targeting the angiotensinogen (AGT) gene, and methods of using such RNAi agents to inhibit expression of AGT and methods of treating subjects having an AGT-associated disorder, e.g., hypertension.

Claims (48)

We claim:
1. A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of ensinogen (AGT) in a cell, wherein the double-stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 uous nucleotides of the tide sequence 5’-UCAUCCACAAUGAGAGUAA-3’ of SEQ ID NO: 679, and the antisense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5’- UUACUCUCAUUGUGGAUGA-3’ of SEQ ID NO: 876, and wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides.
2. The double-stranded RNAi agent of claim 1 , wherein the sense strand is conjugated to a ligand attached at the 3’-terminus.
3. The double-stranded RNAi agent of claim 1 or claim 2, wherein the sense strand ses at least 17 uous nucleotides of the nucleotide sequence 5’- UCAUCCACAAUGAGAGUAA-3’ of SEQ ID NO: 679 and the antisense strand comprise at least 17 uous nucleotides of the nucleotide sequence 5’- UUACUCUCAUUGUGGAUGA-3’ of SEQ ID NO: 876.
4. The double-stranded RNAi agent of claim 1 or claim 2, wherein the sense strand comprises at least 18 contiguous nucleotides of the tide sequence 5’- UCAUCCACAAUGAGAGUAA-3’ of SEQ ID NO: 679 and the antisense strand comprises at least 18 contiguous nucleotides of the nucleotide sequence 5’- UUACUCUCAUUGUGGAUGA-3’ of SEQ ID NO: 876.
5. The double-stranded RNAi agent of any one of claims 2 to 4, wherein at least one of the modified nucleotides is ed from the group consisting of a 3’-terminal deoxythymine (dT) tide, a 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2’-amino-modified nucleotide, a 2’-alkyl-modified tide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5'- phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.
6. The double-stranded RNAi agent of any one of claims 1 to 5, wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide.
7. The double-stranded RNAi agent of any one of claims 1 to 5, wherein at least one strand ses a 3’ overhang of at least 2 nucleotides.
8. The double-stranded RNAi agent of any one of claims 1 to 7, n the double-stranded region is 15-30 nucleotide pairs in length.
9. The double-stranded RNAi agent of any one of claim 1 to 7, wherein the stranded region is 17-23 nucleotide pairs in length.
10. The double-stranded RNAi agent of any one of claims of 1 to 7, wherein the double-stranded region is 17-25 tide pairs in length.
11. The double-stranded RNAi agent of any one of claims 1 to 7, wherein the double-stranded region is 23-27 nucleotide pairs in length.
12. The double-stranded RNAi agent of any one of claims 1 to 7, wherein the double-stranded region is 19-21 nucleotide pairs in length.
13. The double-stranded RNAi agent of any one of claims 1 to 7, wherein the double-stranded region is 21-23 nucleotide pairs in length.
14. The double-stranded RNAi agent of any one of claims 1 to 13, wherein each strand is 15-30 nucleotides in length.
15. The double-stranded RNAi agent of any one of claims 1 to 13, wherein each strand is 19-30 tides in length.
16. The double-stranded RNAi agent of any one of claims 2 to 15, wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.
17. The double-stranded RNAi agent of any one of claims 2 to 15, wherein 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 .
18. The double-stranded RNAi agent of any one of claims 2 to 17, wherein the ligand is attached to the 3? end of the sense strand.
19. The double-stranded RNAi agent of any one of claims 2 to 18, n the RNAi agent is ated to the ligand as shown in the following schematic wherein X is O or S.
20. The double-stranded RNAi agent of any one of claims 1 to 19, wherein the RNAi agent further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
21. The double-stranded RNAi agent of claim 20, wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3’-terminus of one strand.
22. The double-stranded RNAi agent of claim 21, wherein the strand is the antisense strand.
23. The double-stranded RNAi agent of claim 21, wherein the strand is the sense
24. The double-stranded RNAi agent of claim 20, wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5’-terminus of one strand.
25. The double-stranded RNAi agent of claim 24, wherein the strand is the antisense strand.
26. The double-stranded RNAi agent of claim 24, wherein the strand is the sense
27. The double-stranded RNAi agent of claim 20, wherein the phosphorothioate or methylphosphonate ucleotide linkage is at both the 5’- and 3’-terminus of one strand.
28. The double-stranded RNAi agent of claim 27, n the strand is the antisense strand.
29. The double-stranded RNAi agent of claim 20, n the RNAi agent comprises 6-8 phosphorothioate internucleotide linkages.
30. The double-stranded RNAi of claim 29, wherein the antisense strand comprises two phosphorothioate ucleotide linkages at the 5’-terminusand two phosphorothioate internucleotide linkages at the 3’-terminus, and the sense strand comprises at least two phosphorothioate internucleotide linkages at either the 5’-terminus or the 3’-terminus.
31. The double-stranded RNAi agent of claim 1 or claim 2, wherein the base pair at the 1 position of the 5?-end of the nse strand is an AU base pair.
32. A double-stranded ribonucleic acid (RNAi) agent for inhibiting expression of angiotensinogen (AGT), wherein the double-stranded RNAi agent comprises a sense strand and an nse strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence UCCACAAUGAGAGUAA-3’ of SEQ ID NO:679, and the antisense strand comprises at least 15 contiguous tides of the nucleotide sequence 5’- UUACUCUCAUUGUGGAUGA-3’ of SEQ ID NO:876, wherein substantially all of the nucleotides of the sense strand comprise a modification selected from the group consisting of a 2’-O-methyl modification and a 2’-fluoro modification, wherein the sense strand comprises two phosphorothioate internucleotide linkages at the 5’-terminus, wherein ntially all of the nucleotides of the antisense strand comprise a modification selected from the group consisting of a 2’-O-methyl modification and a 2’-fluoro modification, n the antisense strand comprises two phosphorothioate internucleotide linkages at the 5’-terminus and two phosphorothioate internucleotide linkages at the 3’-terminus, and wherein the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3’-terminus.
33. The double -stranded RNAi agent of claim 32, wherein all of the nucleotides of the sense strand and all of the tides of the antisense strand se a modification.
34. An isolated cell containing the double-stranded RNAi agent of any one of claims 1 to 33.
35. A pharmaceutical composition comprising the double-stranded RNAi agent of any one of claims 1 to 33.
36. The pharmaceutical composition of claim 35, wherein double-stranded RNAi agent is formulated in an unbuffered solution.
37. The pharmaceutical ition of claim 36, wherein the unbuffered solution is saline or water.
38. The pharmaceutical composition of claim 35, wherein the double-stranded RNAi agent is formulated in a buffer solution.
39. The ceutical composition of claim 38, wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
40. Use of a therapeutically effective amount of the double-stranded RNAi agent of any one of claims 1 to 33 or the pharmaceutical composition of any one of claims 35 to 39 in the manufacture of a medicament for ng a subject having a angiotensinogen (AGT)- associated disorder.
41. Use of a therapeutically effective amount of a double-stranded ribonucleic acid (RNAi) agent, wherein the -stranded RNAi agent comprises a sense strand and an antisense strand g a -stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5’-UCAUCCACAAUGAGAGUAA-3’ of SEQ ID NO: 679, and the antisense strand comprises at least 15 contiguous nucleotides of the nucleotide sequence 5’- UUACUCUCAUUGUGGAUGA-3’ of SEQ ID NO:876, wherein substantially all of the nucleotides of the antisense strand comprise a modification selected from the group consisting of a 2’-O-methyl modification and a 2’-fluoro modification, wherein the antisense strand comprises two phosphorothioate internucleotide linkages at the 5’-terminus and two phosphorothioate internucleotide linkages at the 3’-terminus, wherein substantially all of the tides of the sense strand comprise a modification selected from the group ting of a 2’-O-methyl modification and a 2’-fluoro modification, n the sense strand comprises two phosphorothioate internucleotide linkages at the 5’-terminus and, n the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3’-terminus,in the manufacture of a medicament for treating a subject having a angiotensinogen (AGT)-associated er, wherein the double-stranded RNAi agent is formulated for subcutaneous administration.
42. The use of claim 41, wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand se a modification.
43. The use of claim 41 or claim 42, wherein the angiotensinogen-associated disease is selected from the group consisting of hypertension, borderline hypertension, primary hypertension, secondary hypertension, hypertensive emergency, hypertensive urgency, isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt hypertension, ocular hypertension, ma, ary hypertension, portal hypertension, systemic venous hypertension, ic hypertension, labile hypertension; hypertensive heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vasculopathy, ic nephropathy, diabetic retinopathy, chronic heart e, myopathy, diabetic cardiac myopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurism, ventricular fibrosis, Cushing’s syndrome, and other glucocorticoid excess states including chronic steroid therapy, romocytoma, reninoma, secondary aldosteronism and other mineralocorticoid excess states, sleep apnea, thyroid/parathyroid disease, heart failure, myocardial infarction, angina, stroke, diabetes mellitus, renal e, renal failure, ic sclerosis, intrauterine growth restriction , and fetal growth restriction.
44. The use of claim 41 or claim 42, wherein the angiotensinogen-associated disease is pregnancy-associated hypertension.
45. The use of any one of claims 41 to 44, wherein the double-stranded RNAi agent is formulated to be administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg.
46. The use of claim 45, wherein the RNAi agent is formulated to be administered in two or more doses.
47. The use of claim 41 or claim 42, wherein the -stranded RNAi agent is formulated to be stered with an additional therapeutic agent.
48. The use of claim 47, wherein the additional therapeutic agent is selected from the group consisting of a diuretic, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a beta-blocker, a vasodilator, a calcium channel blocker, an erone antagonist, an alpha2-agonist, a renin inhibitor, an alpha-blocker, a peripheral acting adrenergic agent, a ive D1 receptor partial agonist, a nonselective alphaadrenergic antagonist, a synthetic, steroidal antimineralocorticoid agent, or a combination of any of the foregoing, and a hypertension therapeutic agent formulated as a combination of agents. .OE mmOFOxE wk<430mm .I._.O< Az_mn_mzkm<0200mw _. wZOmwkw004< .m_N_Oww ._>_D_wm<._.On_ .§3_mmZO<_>_ .Z_wmmmn_0m<> .ZZOFOEMm .mm_2__>_<._OI0m_._.<0 Z_._m_I.rODZm_ z_zmm-zoz M__ A m_wm_I._.Z>w MWMQW?w/w wwog HZO_w.,wm_N_n_Xm ._.O_OZ< ._<_mm.rm< _<._OIOm_._. ZMOOZ_me_._.O_OZ< Zm0<.300 : __ umhumrrm. +02 MJOWDE-I._.OO—>_w-m Dmm 3sz Z_m2m_._.O_OZ< .+v_ wo a a Z_ >._._>_.:wzmw m _| _| F._.< MZOmmeODJ/x mm _| XDIEZ. o_mm<._o Om... ”mkommmm UAN_<._DOm<> mowmwma MZOFOZDHEEH. mmOH_m_IZ_ oz< Omw QZ< EDEOm mmo:m__._z_ + m0< O<_Dm<0v me $4.50 MmOZ<_._n=>_OO Z_Z_¥>D:o xm OEEZ ZO_._.<.__DOm<> OZ_I_m_DO_>_wm_;._.Z< -w_wm_m3_m._. SUBSTITUTE SHEET (RULE 26) ! _ kis. .0_n_ <_mDZ__>_Dm._< \._ ._Om:.ZOO mm QZ< (p/?wNIanNIwnmv mmemmmm _.N 000.5 e “.0 9. ZOEODQmm NF m2: zoE?mmw m .GE JONFZOO _ Mn. mm .0. -o- SUBSTITUTE SHEET (RULE 26) ‘k FIG. ‘— O VVVVVVVVVVVVVVV VVVVV aaaaaaaaaaaaaa °°. (Q <1" N Q OOOOO (((((((( VLNEI TTTTTTTTTTTTTTTTTTTTTTT E PE Z 48 D. FIG. BARRIER CONTROL PLACENTAL 0. Ln. ca we 0. N ‘- 1— O 0 (MI) 38L 01 GBZHVWHON NOISSEHdXE VNHUJ LOVH ENTER SiRNA o: RNAi 2 PE _l 4A Z in < CONTROL FIG. o. to. o. m. o. N 1— x— O 0 (WV) 98L 01 Gaznvwaorxl IHdXE VNHUU iEDVH SUBSTITUTE SHEET (RULE 26) TISSUE EXPOSURE 100000 10000 (ng TESSUE RE g 1000 STRAND/ 100 DRUG ANTiSENSE 10 MATERNAL LTVER PLACENTA FETAL LEVER TESSUE SUBSTITUTE SHEET (RULE 26) mdmoma Es Ikzmm>m<4 Bozsg nw 22¢ mmomdj $35.20me mm. 0... Z_._.o use m0...— w02<10xm 22 I coo— Dwz_<._.w 4 §\N.“kw“ \Mm.~\\\\\\. a
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