US2023069235A1PendingUtilityA1
Methods and compositions for the specific inhibition of alpha-1 antitrypsin by double-stranded rna
Est. expiryJul 3, 2033(~6.9 yrs left)· nominal 20-yr term from priority
C12N 15/113C12N 2310/14C12N 2310/11C12N 2310/321C12N 2310/3233A61P 1/16A61P 35/00C12N 2310/343
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PatentIndex Score
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Claims
Abstract
This invention relates to compounds, compositions, and methods useful for reducing α-1 antitrypsin target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.
Claims
exact text as granted — not AI-modified1 - 68 . (canceled)
69 . A method for treating or preventing a liver or lung disease or disorder in a subject comprising administering to the subject a double stranded nucleic acid (dsNA) comprising first and second nucleic acid strands, wherein the first strand is 36 nucleotides in length and the second strand is 22 nucleotides in length, wherein the second strand is complementary to at least 19 contiguous nucleotides of the α-1 antitrypsin target mRNA and has a sequence of at least 19 consecutive nucleotides of SEQ ID NO: 358, and wherein said liver disease or disorder is selected from the group consisting of chronic liver disease, liver inflammation, cirrhosis, liver fibrosis and hepatocellular carcinoma, and said lung disease or disorder is selected from the group consisting of emphysema, COPD (chronic obstructive pulmonary disease), and cirrhosis.
70 . The method of claim 69 , wherein the first strand comprises a single stranded tetraloop having a sequence of GAAA; and wherein the tetraloop is attached to a moiety selected from the group consisting of a GalNAc moiety, a cholesterol moiety, and a cholesterol targeting ligand.
71 . The method of claim 70 , wherein the tetraloop is attached to a GalNAc moiety.
72 . The method of claim 69 , wherein the dsNA comprises at least one phosphorothioate linkage; and one or more modified nucleotides containing a 2′ modification.
73 . The method of claim 72 , wherein the first strand comprises one phosphorothioate linkage; and the second strand comprises five phosphorothioate linkages; and wherein the one or more modified nucleotides are selected from a 2′-O-methyl nucleotide and a 2′-fluoro nucleotide.
74 . The method of claim 69 , wherein the first strand and the second strand form a duplex such that the second strand comprises a two nucleotide overhang at its 3′ end.
75 . The method of claim 69 , wherein the dsNA comprises a duplex of 19-21 base pairs or 21-25 base pairs in length.
76 . The method of claim 69 , wherein the dsNA comprises a duplex of at least 25 base pairs in length.
77 . The method of claim 69 , wherein said second strand is complementary to 20 contiguous nucleotides of the α-1 antitrypsin target mRNA and has a sequence of 20 consecutive nucleotides of SEQ ID NO: 358.
78 . The method of claim 69 , wherein said second oligonucleotide strand comprises 1-3 single-stranded nucleotides at its 3′ terminus.
79 . The method of claim 72 , wherein the one or more modified nucleotides are selected from the group consisting of 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro, 2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH 2 —O-2′-bridge, 4′-(CH 2 )2-O-2′-bridge, 2′-LNA, 2′-amino, and 2′-O—(N-methylcarbamate).
80 . A method for treating or preventing a liver or lung disease or disorder in a subject, wherein said liver disease or disorder is selected from the group consisting of chronic liver disease, liver inflammation, cirrhosis, liver fibrosis and hepatocellular carcinoma, and said lung disease or disorder is selected from the group consisting of emphysema, COPD (chronic obstructive pulmonary disease), and cirrhosis, the method comprising administering to the subject a double stranded nucleic acid (dsNA) comprising first and second nucleic acid strands, wherein said first strand is 15-53 nucleotides in length and said second strand is 19-35 nucleotides in length, wherein said second strand is complementary to at least 19 contiguous nucleotides of the α-1 antitrypsin target mRNA and has a sequence of at least 19 consecutive nucleotides of SEQ ID NO: 358, wherein said dsNA reduces α-1 antitrypsin target mRNA expression when introduced into a mammalian cell, and wherein said second strand comprises a modification pattern selected from the following:
AS-M1 3′- XXX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M2 3′- XXX X X X XX XXXX XX X X X X XXXXXXXX X -5′
AS-M3 3′- XXX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M4 3′- XXX X X X X XXXXXX X X X X X XXXXXXX XX -5′
AS-M5 3′- XXX X X XXXXXXXX X X X X X XXXXXXX XX -5′
AS-M6 3′- X X X XXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M7 3′- XX XXXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M8 3′- XXX X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M9 3′-XXX X X XX XXXX XX XX X XXXXXXXXXXX-5′
AS-M10 3′- XX X XX X X XXXXXXXXXX XX XXXX XXXX -5′
AS-M11 3′- X X X XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M12 3′- X X X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M13 3′- XX XX X XXXXXXXXXX X XXXXXXXXX XX -5′
AS-M14 3′- XX XX X XX XX XXXXXX X XXXXXXXXX XX -5′
AS-M15 3′- XX XXXXXXXXXXXXX X XXXXXXXXX XX -5′
AS-M16 3′- XX XX XX X X X X XXXXXXX XX XXXX XXXX -5′
AS-M17 3′- XXX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M18 3′- XX XX X XX X XXXXXXX X XXXXXXXXX XX -5′
AS-M19 3′- XXX X X X X X X X X X X X X X X XXXXXXXX XX -5′
AS-M20 3′- XXX X X X X X X X X X X X X X X XXXXXXXX X X-5′
AS-M21 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M22 3′- XXXX XXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M24 3′- XXX X X X X XXXXXXX XX X X XXXXXXX XX -5′
AS-M25 3′- XXX XXXXXXXXXXX XX X X XXXXXXX XX -5′
AS-M26 3′- XXX X X X X X X X X X X X X X X XXXXXXXXXX-5′
AS-M27 3′- XXX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M28 3′- XXX X X X X XXXXXXXXXXXXXXXXXXXX-5′
AS-M29 3′- XXX XXXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M30 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M31 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M32 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M34 3′- XXX X X X XXX XXX XX X X X X XXXXX XXXX -5′
AS-M35 3′- XXX X X X X X X XXXXX X X X XXXXXX XXXX -5′
AS-M36 3′- XXX X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M37 3′- XXX X X X X XXXXXXXXXXXXXXXXXX XX -5′
AS-M38 3′- XXX X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M40 3′- XXX XXXXXXXXXXXXXXXXXXXXXX XX -5′
AS-M41 3′- XXX X X X X XXXXXXX X X X XXXXXXXXXX-5′
AS-M42 3′- XX XX X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M43 3′- XXX X X XXXXXXXXX XX X X XXXXX XXXX -5′
AS-M44 3′- XXX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M45 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M46 3′- XXX X X X X X X X X X X X X X X X X X X X X X X X X -5′
AS-M47 3′- X X X X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M48 3′- XXX X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M52 3′- XXX X X X X X X X X X X X X X X X X X X X XXXXX -5′
AS-M54 3′- XXX X X XXXXXXXXX X X X X X XXXX XXXX -5′
AS-M55 3′- XXX X X XXXXXXX X X X X X XXXXXX XXXX -5′
AS-M56 3′- XXX X X X X XXXXXXX X X X X X XXXX XXXX -5′
AS-M57 3′- XXX X X X X XXXXX X X X X X XXXXXX XXXX -5′
AS-M58 3′- XXX X X XXXXXXX X X X X X X X XXXX XXXX -5′
AS-M59 3′- XXX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M60 3′- XXX X X X X XXXXXXX X X X XXXXX XXXXX -5′
AS-M61 3′- XXXXX XXXXXXXXX X X XXXX XXX XXXX -5′
AS-M62 3′- XXXXX XXXXXXXXX X X XXXX XXXX XXX -5′
AS-M63 3′- XXX X X X X X X XXXXX X X X X X XXXX XXXX -5′
AS-M64 3′- XXX X X X X X X XXX X X X X X X X XXXX XXXX -5′
AS-M65 3′- XXXXX XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M66 3′- XXXXXX XXXXXXXX X X X XXXXXX XXXX -5′
AS-M67 3′- XXX X X X XX XXXXXX X X X XXXXXX XXXX -5′
AS-M68 3′- XXX X X XXXXXXXX XXXX XXXXXX XXXX -5′
AS-M69 3′- XXX X X XXXXXXXX XXXXX XXXXX XXXX -5′
AS-M70 3′- XXXXX XXXXXXXXX XXX XXXXXX XXXX -5′
AS-M71 3′- XXX X X XXXXXXXX XX X XX XXXXX XXXX -5′
AS-M72 3′- XXX X X XXXXXXX X X X X X XX X XXX XXXX -5′
AS-M73 3′- XXX X XX XXXXXXXX X X XX XXXXX XXXX -5′
AS-M74 3′- XXX X X XXXXXXXX XX X X XXXXXX XXXX -5′
AS-M75 3′- XXX X X XXXXXXX X X XXX XXXXXX XXXX -5′
AS-M76 3′- XXX X X XXXXXXX X X XXXX X X XX XXXXX -5′
AS-M77 3′- XXX X X XXXXXXXXX XXXX XXXXX XXXX -5′
AS-M78 3′- XXX X X X X XXXXXXXX X X X XXXXX XXXX -5′
AS-M79 3′- XXX X X X XX XXXXXXXX XX XXXXX XXXX -5′
AS-M80 3′- XXX X X XXXXXXXXX XXX X X XXXX XXXX -5′
AS-M81 3′-XX X X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M82 3′- X p XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M83 3′- X p XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M84 3′- X X X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M85 3′-XXXX X XXXXXXXX X XXXXXXXXX XXXX -5′
AS-M88 3′-FFFX X X X X X X X X X X X X X XXXXXXFFFF-5′
AS-M89 3′- XXX XFX X XFXF X X X X X XXXXXXX XXXX -5′
AS-M90 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M91 3′-FFFX X X X XXXXX X X X X X X X XXXX XX FF-5′
AS-M92 3′- XXX X X XFXXXXXFXFX X X X XXXX XXXX -5′
AS-M93 3′-FFFXFX X XXXXX X X X X X XFXXXX XXXX -5′
AS-M94 3′-FFFXFXFXXXXXFXFXFXFXXXXFFFF-5′
AS-M95 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M96 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′
AS-M210 3′- X X X X X X X X X X X X X X X X X X X X X XX XXXX -5′
AS-M1* 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M2* 3′-X XX X X X XX XXXX XX X X X X XXXXXXXX X -5′
AS-M3* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M4* 3′-X XX X X X X XXXXXX X X X X X XXXXXXX XX -5′
AS-M5* 3′-X XX X X XXXXXXXX X X X X X XXXXXXXX X -5′
AS-M6* 3′-XX X XXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M7* 3′-X X XXXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M8* 3′-X XX X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M9* 3′-XXX X X XX XXXX XX XX X XXXXXXXXXXX-5′
AS-M10* 3′-X X X XX X X XXXXXXXXXX XX XXXX XXXX -5′
AS-M11* 3′-XX X XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M12* 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M13* 3′-X X XX X XXXXXXXXXX X XXXXXXXXX XX -5′
AS-M14* 3′-X X XX X XX XX XXXXXX X XXXXXXXXX XX -5′
AS-M15* 3′-X X XXXXXXXXXXXXX X XXXXXXXXX XX -5′
AS-M16* 3′-X X XX XX X X X X XXXXXXX XX XXXX XXXX -5′
AS-M17* 3′-X XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M18* 3′-X X XX X XX X XXXXXXX X XXXXXXXXX XX -5′
AS-M19* 3′-X XX X X X X X X X X X X X X X X XXXXXXXX XX -5′
AS-M20* 3′-X XX X X X X X X X X X X X X X X XXXXXXXX X X-5′
AS-M21* 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M22* 3′-X XXX XXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M24* 3′-X XX X X X X XXXXXXX XX X X XXXXXXX XX -5′
AS-M25* 3′-X XX X X XXXXXXXXX XX X X XXXXXXX XX -5′
AS-M26* 3′-X XX X X X X X X X X X X X X X X XXXXXXXXXX-5′
AS-M27* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M28* 3′-X XX X X X X XXXXXXXXXXXXXXXXXXXX-5′
AS-M29* 3′-X XX XXXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M30* 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M31* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M32* 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M34* 3′-X XX X X X XXX XXX XX X X X X XXXXX XXXX -5′
AS-M35* 3′-X XX X X X X X X XXXXX X X X XXXXXX XXXX -5′
AS-M36* 3′-X XX X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M37* 3′-X XX X X X X XXXXXXXXXXXXXXXXXX XX -5′
AS-M38* 3′-X XX X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M40* 3′-X XX XXXXXXXXXXXXXXXXXXXXXX XX -5′
AS-M41* 3′-X XX X X X X XXXXXXX X X X XXXXXXXXXX-5′
AS-M42* 3′-X X XX X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M43* 3′-X XX X X XXXXXXXXX XX X X XXXXX XXXX -5′
AS-M44* 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M45* 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M46* 3′-X XX X X X X X X X X X X X X X X X X X X X X X X X X -5′
AS-M47* 3′-X X X X XXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M48* 3′-X XX X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M52* 3′-X XX X X X X X X X X X X X X X X X X X X X XXXXX -5′
AS-M54* 3′-X XX X X XXXXXXXXX X X X X X XXXX XXXX -5′
AS-M55* 3′-X XX X X XXXXXXX X X X X X XXXXXX XXXX -5′
AS-M56* 3′-X XX X X X X XXXXXXX X X X X X XXXX XXXX -5′
AS-M57* 3′-X XX X X X X XXXXX X X X X X XXXXXX XXXX -5′
AS-M58* 3′-X XX X X XXXXXXX X X X X X X X XXXX XXXX -5′
AS-M59* 3′-X XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M60* 3′-X XX X X X X XXXXXXX X X X XXXXX XXXXX -5′
AS-M61* 3′-X XXXX XXXXXXXXX X X XXXX XXX XXXX -5′
AS-M62* 3′-X XXXX XXXXXXXXX X X XXXX XXXX XXX -5′
AS-M63* 3′-X XX X X X X X X XXXXX X X X X X XXXX XXXX -5′
AS-M64* 3′-X XX X X X X X X XXX X X X X X X X XXXX XXXX -5′
AS-M65* 3′-X XXXX XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M66* 3′-X XXXXX XXXXXXXX X X X XXXXXX XXXX -5′
AS-M67* 3′-X XX X X X XX XXXXXX X X X XXXXXX XXXX -5′
AS-M68* 3′-X XX X X XXXXXXXX XXXX XXXXXX XXXX -5′
AS-M69* 3′-X XX X X XXXXXXXX XXXXX XXXXX XXXX -5′
AS-M70* 3′-X XXXX XXXXXXXXX XXX XXXXXX XXXX -5′
AS-M71* 3′-X XX X X XXXXXXXX XX X XX XXXXX XXXX -5′
AS-M72* 3′-X XX X X XXXXXXX X X X X X XX X XXX XXXX -5′
AS-M73* 3′-X XX X XX XXXXXXXX X X XX XXXXX XXXX -5′
AS-M74* 3′-X XX X X XXXXXXXX XX X X XXXXXX XXXX -5′
AS-M75* 3′-X XX X X XXXXXXX X X XXX XXXXXX XXXX -5′
AS-M76* 3′-X XX X X XXXXXXX X X XXXX X X XX XXXXX -5′
AS-M77* 3′-X XX X X XXXXXXXXX XXXX XXXXX XXXX -5′
AS-M78* 3′-X XX X X X X XXXXXXXX X X X XXXXX XXXX -5′
AS-M79* 3′-X XX X X X XX XXXXXXXX XX XXXXX XXXX -5′
AS-M80* 3′-X XX X X XXXXXXXXX XXX X X XXXX XXXX -5′
AS-M81* 3′-XX X X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M82* 3′-Xp XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M83* 3′-Xp XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M84* 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M85* 3′-XXXX X XXXXXXXX X XXXXXXXXX XXXX -5′
AS-M88* 3′-XFFX X X X X X X X X X X X X X XXXXXXFFFF-5′
AS-M89* 3′-X XX XFX X XFXFX X X X X X XXXXXX XXXX -5′
AS-M90* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M91* 3′-XFFX X X X XXXXX X X X X X X X XXXX XX FF-5′
AS-M92* 3′-X XX X X XFXXXXXFXFX X X X XXXX XXXX -5′
AS-M93* 3′-XFFXFX X XXXXX X X X X X XFXXXX XXXX -5′
AS-M94* 3′-XFFXFXFXXXXXFXFXFXFXXXXFFFF-5′
AS-M95* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M96* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′
AS-M210* 3′-XX X X X X X X X X X X X X X X X X X X X XX XXXX -5′
wherein “X”=RNA, “ X ”=2′-O-methyl RNA, “F”=2′-Fluoro NA and “p”=Phosphorothioate linkage.
81 . The method of claim 80 , wherein said first strand comprises a modification pattern selected from the following:
“SM1” 5′-X X XX X XXXXX X XXX X XXXXX X XXDD-3′
“SM2” 5′- X XXXXXXXXXX X XXXXXXXXXXXDD-3′
“SM3” 5′-XX X XX X X X X X XXXXXX XX XXXXXDD-3′
“SM4” 5′-XXX X XX X X X XXX XX X X XX XX XXXDD-3′
“SM5” 5′-XXXXXXXXXXXXXXXXXX XXXX XDD-3′
“SM6” 5′-XXXXXXXXXXXXX XXXXX XXXXXDD-3′
“SM7” 5′-X X XX X XXXXXX X XX X XXXXXXXXDD-3′
“SM8” 5′-XX X X X XXXXXXX X X X XXXXXXXXDD-3′
“SM9” 5′-XX X XXXXX X XXX X XXXXX X XX X XDD-3′
“SM10” 5′-XXXXXXXX X XXXXXXXXXX X XX X DD-3′
“SM11” 5′- X XX X X X X X XXXXXX XX XXXXXXXDD-3′
“SM12” 5′-X X XX X X X XXX XX X X XX XX XXXXXDD-3′
“SM13” 5′-XX X X X XXXXXXX X XXXXX XX XXXDD-3′
“SM14” 5′-X X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM15” 5′- XXX XXXXXXXXXXXX XXX XXXXXDD-3′
“SM16” 5′- XX X X X X X X XXX X X X X X X X XXXX X DD-3′
“SM17” 5′- XX X X X X X X XXX X X XXX X X X X XX X DD-3′
“SM18” 5′- X XX X X X X X XXXXXX XX XX X XXXXDD-3′
“SM19” 5′- X XX X X X X X XXXXXX XX XX X XX X XDD-3′
“SM20” 5′- XX X X X X X X XXX X X X X X X XX XX X XDD-3′
“SM21” 5′-X X X X X X X X X X X X X X X X X X XXXXXDD-3′
“SM23” 5′-X X X X X X X X XXX X X X X X X XX XXX X DD-3′
“SM24” 5′- XX X X X XX XXXX X X X X X X XX XXX X DD-3′
“SM25” 5′- XX X X X X X X X X X X X X X X X X X X XXXDD-3′
“SM30” 5′- XX X X X X X X X X X X X X X X X X X X X X XDD-3′
“SM31” 5′- X XX X X X XXXXX X XX X XX X XXXX X DD-3′
“SM32” 5′-X X X X X XX XXXX X X X X X X XX XXX X DD-3′
“SM33” 5′- XX X X X XX XXXX X X X X X X XX XXXXDD-3′
“SM34” 5′-X XX X X X X XXX XX X X XX XX X X XXXDD-3′
“SM35” 5′-X X XX X X XX XX XX X X XX XX XXXX X DD-3′
“SM36” 5′-X XX X X X XX XX XX X X XX XX X X XX X DD-3′
“SM37” 5′-X X X XXX X X XXX X X X X X X X XXXXXDD-3′
“SM38” 5′-X X X X X X X X XXX X X X X XXX XXXXXDD-3′
“SM39” 5′-X X X XXX X X XXX X X X X XXX X X XXXDD-3′
“SM40” 5′-X X X XXXXX XX XX X X X XXX X X XX X DD-3′
“SM41” 5′-X X X X X X X X XXX X X X X X X X X XX XXDD-3′
“SM42” 5′- XXXXXXX XXXX X X X X X X XX XXX X DD-3′
“SM43” 5′- XXXXXXX XXXX X X X X X X X XXXX X DD-3′
“SM44” 5′-X X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM45”, 51-X XX X X X X XXX XX X X X XXXX XXXXDD-3′
“SM47” “SM46” 5′-X XX X XXX XXX XXXX X XXX XXXXXDD-3′
“SM48” 5′-X X X XX X X XXX XX X XX X XX X X XXXDD-3′
“SM49” 5′- XX XX XXX XXX XX X X XX XXX XXXXDD-3′
“SM50” 5′-X X X XX X X XXX XX X XX X XXX XXXXDD-3′
“SM51” 5′-X X XX XXX XXX XX X XX X XX XXXX X DD-3′
“SM52” 5′-X XXX X XXX XXX X X X X X X XX XXXXDD-3′
“SM53” 5′-X X X X X XX XXXX X X XXX X XX XXX X DD-3′
“SM54” 5′- XX X X X XX XXXX X X XXX X XX XXX X DD-3′
“SM55” 5′-X X XX X X X XXX XXXX XX XXX XXXXDD-3′
“SM56” 5′-X XX X XXX XXX XX X X X XXX XXXXXDD-3′
“SM57” 5′-X XXX X XXX XXX X X X X X X X XXXX X DD-3′
“SM58” 5′-X XX X X X X XXX XX X XX X XX XXXXXDD-3′
“SM59” 5′-X X X XX X XX XXX X X X X XXX XXXXXDD-3′
“SM60” 5′-X XX X X X X XXX XXXX XX XX X X XXXDD-3′
“SM61” 5′-X X X XX X X XXX XXXX X XXX XXXXXDD-3′
“SM62” 5′-X X X XX X X XXX XX X X X XXXX XXXXDD-3′
“SM63” 5′-X XXX X XXX XXX XXX X X X X XXXXXDD-3′
“SM64” 5′-X X X XX X X XXXX X XX X XX X XXXXXDD-3′
“SM65” 5′-XXX X X X X X XXX X X X X X X X XXXXXDD-3′
“SM66” 5′-X X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM67” 5′-Xp X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM68” 5′-Xp X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM69” 5′-D X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM70” 5′-Dp X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM71” 5′-D X D X X X X X XXX X X X X X X X XXXXXDD-3
“SM72” 5′-Dp X D X X X X X XXX X X X X X X X XXXXXDD-3′
“SM73” 5′-X X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM74” 5′-Xp X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM75” 5′-D X D X X X X X XXX X D X X X X X DXXXXDD-3′
“SM76” 5′-Dp X D X X X X X XXX X D X X X X X DXXXXDD-3′
“SM77” 5′-Xp Xp X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM78” 5′-Xp Xp X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM79” 5′-Dp Xp D X X X X X XXX X X X X X X X XXXXXDD-3′
“SM80” 5′-Xp Xp D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM81” 5′-D X D X X X D X XXX X D X X X X X DXXXXDD-3′
“SM82” 5′-Dp X D X X X D X XXX X D X X X X X DXXXXpDpD-3′
“SM83” 5′C3 spacer-X X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM84” 5′C3 spacer-X X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM85” 5′C3 spacer-X X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM86” 5′-X X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM87” 5′-Xp X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM88” 5′-Xp X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM89” 5′-D X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM90” 5′-Dp X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM91” 5′-D X D XXX X X XXX X X X X XXX XXXXXDD-3′
“SM92” 5′-Dp X D XXX X X XXX X X X X XXX XXXXXDD-3′
“SM93” 5′-X X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM94” 5′-Xp X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM95” 5′-D X D XXX X X XXX X D X X XXX DXXXXDD-3′
“SM96” 5′-Dp X D XXX X X XXX X D X X XXX DXXXXDD-3′
“SM97” 5′-Xp X pX XXX X X XXX X X X X XXX XXXXXDD-3′
“SM98” 5′-Xp X pX XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM99” 5′-Dp X pD XXX X X XXX X X X X XXX XXXXXDD-3′
“SM100” 5′-Xp X pD XXX X X XXX X D X X XXX XXXXXDD-3′
“SM101” 5′-D X D XXX X X XXX X D X D XXX DDXXDDD-3′
“SM102” 5′-Dp X D XXX D X XXX X D X X XXX DXXXXpDpD-3′
“SM103” 5′C3 spacer-X X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM104” 5′C3 spacer-X X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM105” 5′C3 spacer-X X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM106” 5′- X X X X X X X X X X X X X X X X X X X XXXXDD-3′
“SM107” 5′-X X X X XXXXXXXXX X X X XXXXXXXDD-3′
“SM108” 5′-XXX X XXXXX X XXX X XXX X XXXXXDD-3′
“SM110” 5′-XFX X X X X X XXX X X X X X XFXXXXXDD-3′
“SM111” 5′-X X XFXFX X XXX X XFX X X X XXXXXDD-3′
“SM112” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′
“SM113” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′0
“SM114” 5′-XFX XXX X X XXX X X X X XXX XXXXXDD-3
“SM115” 5′-X X X X FFXFXXXFXFX XXX XXXXXDD-3
“SM116” 5′-XFXF XX X X XXX X X X X X F X XXXXXDD-3
“SM117” 5′-XFXFFFXFXXXFXFXFFFXXXXXDD-3
“SM118” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3
“SM119” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′
“SM250” 5′-X X X X X X XXXXXXX X X X X X XXXXXDD-3
“SM251” 5′-X X X X X XX XXXXX XX X X X XX XXX X DD-3′
“SM252” 5′-X X X X X X X X XX X X XX X X X X X X XX X DD-3′
5′-X X XX X XXXXX X XXX X XXXXX X XXXX-3′
5′- X XXXXXXXXXX X XXXXXXXXXXXXX-3′
5′-XX X XX X X X X X XXXXXX XX XXXXXXX-3′
5′-XXX X XX X X X XXX XX X X XX XX XXXXX-3′
5′-XXXXXXXXXXXXXXXXXX XXXX XXX-3′
5′-XXXXXXXXXXXXX XXXXX XXXXXXX-3′
5′-X X XX X XXXXXX X XX X XXXXXXXXXX-3′
5′-XX X X X XXXXXXX X X X XXXXXXXXXX-3′
5′-XX X XXXXX X XXX X XXXXX X XX X XXX-3′
5′-XXXXXXXXX X XXXXXXXXX X XX X XX-3′
5′- X XX X X X X X XXXXXX XX XXXXXXXXX-3′
5′-X X XX X X X XXX XX X X XX XX XXXXXXX-3′
5′-XX X X X XXXXXXX X XXXXX XX XXXXX-3′
5′-X X X X X X X X XXX X X X X X XXXXXXXXX-3′
5′- XXX XXXXXXXXXX XXX XXXXXXXXX-3′
5′- XX X X X X X X X X X X X X X X XXXXXXXXX-3′
5′- XX X X X X X X XXX X X XXX X X X X XX X XX-3′
5′- X XX X X X X X XXXXXX XX XX X XXXXXX-3′
5′- X XX X X X X X XXXXXX XX XX X XX X XXX-3′
5′- XX X X X X X X XXX X X X X X X XX XXX X XX-3′
5′-X X X X X X X X X X X X X X X X X X XXXXXXX-3′
5′-X X X X X X X X XXX X X X X X X XX XXX X XX-3′
5′- XX X X X XX XXXX X X X X X X XX XXX X XX-3′
5′- XX X X X X X X X X X X X X X X X X X X XXXXX-3′
5′- XX X X X X X X X X X X X X X X X X X X X X XXX-3′
5′- X XX X X X XXXXX X XX X XX X XXXX X XX-3′
5′-X X X X X XX XXXX X X X X X X XX XXX X XX-3′
5′- XX X X X XX XXXX X X X X X X XX XXXXXX-3′
5′-X XX X X X X XXX XX X X XX XX X X XXXXX-3′
5′-X X XX X X XX XX XX X X XX XX XXXX X XX-3′
5′-X XX X X X XX XX XX X X XX XX X X XX X XX-3′
5′-X X X XXX X X XXX X X X X X X X XXXXXXX-3′
5′-X X X X X X X X XXX X X X X XXX XXXXXXX-3′
5′-X X X XXX X X XXX X X X X XXX X X XXXXX-3′
5′-X X X XXXXX XX XX X X X XXX X X XX X XX-3′
5′-X X X X X X X X XXX X X X X X X X X XX XXXX-3′
5′- XXXXXXX XXXX X X X X X X XX XXX X XX-3′
5′- XXXXXXX XXXX X X X X X X X XXXX X XX-3′
5′-X X X XXX X X XXX X X X X XXX XXXXXXX-3′
5′-X XX X X X X XXX XX X X X XXXX XXXXXX-3′
5′-X XX X XXX XXX XXXX X XXX XXXXXXX-3′
5′-X X X XX X X XXX XX X XX X XX X X XXXXX-3′
5′- XX XX XXX XXX XX X X XX XXX XXXXXX-3′
5′-X X X XX X X XXX XX X XX X XXX XXXXXX-3′
5′-X X XX XXX XXX XX X XX X XX XXXX X XX-3′
5′-X XXX X XXX XXX X X X X X X XX XXXXXX-3′
“SM22” 5′-X X X X X X X X X X X X X X X X X X X X X X X XX -3′
5′-X X X X XXXXXXXXX X X X XXXXXXXXX-3′
5′-X X X X X XX XXXXX XX X X X XX XXX X XX-3′
5′-X X X X X X X X XX X X XX X X X X X X XX X XX-3′
wherein “X”=RNA, “ X ”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and “p”=Phosphorothioate linkage.
82 . A method for reducing expression of a target α-1 antitrypsin mRNA in a mammal comprising administering to the mammal a double stranded nucleic acid (dsNA) comprising first and second nucleic acid strands, wherein said first strand is 15-53 nucleotides in length and said second strand is 19-35 nucleotides in length, wherein said second strand is complementary to at least 19 contiguous nucleotides of the α-1 antitrypsin target mRNA and has a sequence of at least 19 consecutive nucleotides of SEQ ID NO: 358, wherein said dsNA reduces α-1 antitrypsin target mRNA expression when introduced into a mammalian cell.
83 . The method of claim 82 , wherein said first strand comprises a modification pattern selected from the following:
“SM1” 5′-X X XX X XXXXX X XXX X XXXXX X XXDD-3′
“SM2” 5′- X XXXXXXXXXX X XXXXXXXXXXXDD-3′
“SM3” 5′-XX X XX X X X X X XXXXXX XX XXXXXDD-3′
“SM4” 5′-XXX X XX X X X XXX XX X X XX XX XXXDD-3′
“SM5” 5′-XXXXXXXXXXXXXXXXXX XXXX XDD-3′
“SM6” 5′-XXXXXXXXXXXXX XXXXX XXXXXDD-3′
“SM7” 5′-X X XX X XXXXXX X XX X XXXXXXXXDD-3′
“SM8” 5′-XX X X X XXXXXXX X X X XXXXXXXXDD-3′
“SM9” 5′-XX X XXXXX X XXX X XXXXX X XX X XDD-3′
“SM10” 5′-XXXXXXXX X XXXXXXXXXX X XX X DD-3′
“SM11” 5′- X XX X X X X X XXXXXX XX XXXXXXXDD-3′
“SM12” 5′-X X XX X X X XXX XX X X XX XX XXXXXDD-3′
“SM13” 5′-XX X X X XXXXXXX X XXXXX XX XXXDD-3′
“SM14” 5′-X X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM15” 5′- XXX XXXXXXXXXXXX XXX XXXXXDD-3′
“SM16” 5′- XX X X X X X X XXX X X X X X X X XXXX X DD-3′
“SM17” 5′- XX X X X X X X XXX X X XXX X X X X XX X DD-3′
“SM18” 5′- X XX X X X X X XXXXXX XX XX X XXXXDD-3′
“SM19” 5′- X XX X X X X X XXXXXX XX XX X XX X XDD-3′
“SM20” 5′- XX X X X X X X XXX X X X X X X XX XX X XDD-3′
“SM21” 5′-X X X X X X X X X X X X X X X X X X XXXXXDD-3′
“SM23” 5′-X X X X X X X X XXX X X X X X X XX XXX X DD-3′
“SM24” 5′- XX X X X XX XXXX X X X X X X XX XXX X DD-3′
“SM25” 5′- XX X X X X X X X X X X X X X X X X X X XXXDD-3′
“SM30” 5′- XX X X X X X X X X X X X X X X X X X X X X XDD-3′
“SM31” 5′- X XX X X X XXXXX X XX X XX X XXXX X DD-3′
“SM32” 5′-X X X X X XX XXXX X X X X X X XX XXX X DD-3′
“SM33” 5′- XX X X X XX XXXX X X X X X X XX XXXXDD-3′
“SM34” 5′-X XX X X X X XXX XX X X XX XX X X XXXDD-3′
“SM35” 5′-X X XX X X XX XX XX X X XX XX XXXX X DD-3′
“SM36” 5′-X XX X X X XX XX XX X X XX XX X X XX X DD-3′
“SM37” 5′-X X X XXX X X XXX X X X X X X X XXXXXDD-3′
“SM38” 5′-X X X X X X X X XXX X X X X XXX XXXXXDD-3′
“SM39” 5′-X X X XXX X X XXX X X X X XXX X X XXXDD-3′
“SM40” 5′-X X X XXXXX XX XX X X X XXX X X XX X DD-3′
“SM41” 5′-X X X X X X X X XXX X X X X X X X X XX XXDD-3′
“SM42” 5′- XXXXXXX XXXX X X X X X X XX XXX X DD-3′
“SM43” 5′- XXXXXXX XXXX X X X X X X X XXXX X DD-3′
“SM44” 5′-X X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM45”, 51-X XX X X X X XXX XX X X X XXXX XXXXDD-3′
“SM47” “SM46” 5′-X XX X XXX XXX XXXX X XXX XXXXXDD-3′
“SM48” 5′-X X X XX X X XXX XX X XX X XX X X XXXDD-3′
“SM49” 5′- XX XX XXX XXX XX X X XX XXX XXXXDD-3′
“SM50” 5′-X X X XX X X XXX XX X XX X XXX XXXXDD-3′
“SM51” 5′-X X XX XXX XXX XX X XX X XX XXXX X DD-3′
“SM52” 5′-X XXX X XXX XXX X X X X X X XX XXXXDD-3′
“SM53” 5′-X X X X X XX XXXX X X XXX X XX XXX X DD-3′
“SM54” 5′- XX X X X XX XXXX X X XXX X XX XXX X DD-3′
“SM55” 5′-X X XX X X X XXX XXXX XX XXX XXXXDD-3′
“SM56” 5′-X XX X XXX XXX XX X X X XXX XXXXXDD-3′
“SM57” 5′-X XXX X XXX XXX X X X X X X X XXXX X DD-3′
“SM58” 5′-X XX X X X X XXX XX X XX X XX XXXXXDD-3′
“SM59” 5′-X X X XX X XX XXX X X X X XXX XXXXXDD-3′
“SM60” 5′-X XX X X X X XXX XXXX XX XX X X XXXDD-3′
“SM61” 5′-X X X XX X X XXX XXXX X XXX XXXXXDD-3′
“SM62” 5′-X X X XX X X XXX XX X X X XXXX XXXXDD-3′
“SM63” 5′-X XXX X XXX XXX XXX X X X X XXXXXDD-3′
“SM64” 5′-X X X XX X X XXXX X XX X XX X XXXXXDD-3′
“SM65” 5′-XXX X X X X X XXX X X X X X X X XXXXXDD-3′
“SM66” 5′-X X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM67” 5′-Xp X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM68” 5′-Xp X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM69” 5′-D X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM70” 5′-Dp X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM71” 5′-D X D X X X X X XXX X X X X X X X XXXXXDD-3
“SM72” 5′-Dp X D X X X X X XXX X X X X X X X XXXXXDD-3′
“SM73” 5′-X X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM74” 5′-Xp X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM75” 5′-D X D X X X X X XXX X D X X X X X DXXXXDD-3′
“SM76” 5′-Dp X D X X X X X XXX X D X X X X X DXXXXDD-3′
“SM77” 5′-Xp Xp X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM78” 5′-Xp Xp X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM79” 5′-Dp Xp D X X X X X XXX X X X X X X X XXXXXDD-3′
“SM80” 5′-Xp Xp D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM81” 5′-D X D X X X D X XXX X D X X X X X DXXXXDD-3′
“SM82” 5′-Dp X D X X X D X XXX X D X X X X X DXXXXpDpD-3′
“SM83” 5′C3 spacer-X X X X X X X X XXX X X X X X X X XXXXXDD-3′
“SM84” 5′C3 spacer-X X D X X X X X XXX X D X X X X X XXXXXDD-3′
“SM85” 5′C3 spacer-X X X X X X X X XXX X X X X X X X XXXXXpDpD-3′
“SM86” 5′-X X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM87” 5′-Xp X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM88” 5′-Xp X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM89” 5′-D X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM90” 5′-Dp X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM91” 5′-D X D XXX X X XXX X X X X XXX XXXXXDD-3′
“SM92” 5′-Dp X D XXX X X XXX X X X X XXX XXXXXDD-3′
“SM93” 5′-X X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM94” 5′-Xp X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM95” 5′-D X D XXX X X XXX X D X X XXX DXXXXDD-3′
“SM96” 5′-Dp X D XXX X X XXX X D X X XXX DXXXXDD-3′
“SM97” 5′-Xp X pX XXX X X XXX X X X X XXX XXXXXDD-3′
“SM98” 5′-Xp X pX XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM99” 5′-Dp X pD XXX X X XXX X X X X XXX XXXXXDD-3′
“SM100” 5′-Xp X pD XXX X X XXX X D X X XXX XXXXXDD-3′
“SM101” 5′-D X D XXX X X XXX X D X D XXX DDXXDDD-3′
“SM102” 5′-Dp X D XXX D X XXX X D X X XXX DXXXXpDpD-3′
“SM103” 5′C3 spacer-X X X XXX X X XXX X X X X XXX XXXXXDD-3′
“SM104” 5′C3 spacer-X X D XXX X X XXX X D X X XXX XXXXXDD-3′
“SM105” 5′C3 spacer-X X X XXX X X XXX X X X X XXX XXXXXpDpD-3′
“SM106” 5′- X X X X X X X X X X X X X X X X X X X XXXXDD-3′
“SM107” 5′-X X X X XXXXXXXXX X X X XXXXXXXDD-3′
“SM108” 5′-XXX X XXXXX X XXX X XXX X XXXXXDD-3′
“SM110” 5′-XFX X X X X X XXX X X X X X XFXXXXXDD-3′
“SM111” 5′-X X XFXFX X XXX X XFX X X X XXXXXDD-3′
“SM112” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′
“SM113” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′0
“SM114” 5′-XFX XXX X X XXX X X X X XXX XXXXXDD-3
“SM115” 5′-X X X X FFXFXXXFXFX XXX XXXXXDD-3
“SM116” 5′-XFXF XX X X XXX X X X X X F X XXXXXDD-3
“SM117” 5′-XFXFFFXFXXXFXFXFFFXXXXXDD-3
“SM118” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3
“SM119” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′
“SM250” 5′-X X X X X X XXXXXXX X X X X X XXXXXDD-3
“SM251” 5′-X X X X X XX XXXXX XX X X X XX XXX X DD-3′
“SM252” 5′-X X X X X X X X XX X X XX X X X X X X XX X DD-3′
5′- X XXXXXXXXXX X XXXXXXXXXXXXX-3′
5′-XX X XX X X X X X XXXXXX XX XXXXXXX-3′
5′-XXX X XX X X X XXX XX X X XX XX XXXXX-3′
5′-XXXXXXXXXXXXXXXXXX XXXX XXX-3′
5′-XXXXXXXXXXXXX XXXXX XXXXXXX-3′
5′-X X XX X XXXXXX X XX X XXXXXXXXXX-3′
5′-XX X X X XXXXXXX X X X XXXXXXXXXX-3′
5′-XX X XXXXX X XXX X XXXXX X XX X XXX-3′
5′-XXXXXXXXX X XXXXXXXXX X XX X XX-3′
5′- X XX X X X X X XXXXXX XX XXXXXXXXX-3′
5′-X X XX X X X XXX XX X X XX XX XXXXXXX-3′
5′-XX X X X XXXXXXX X XXXXX XX XXXXX-3′
5′-X X X X X X X X XXX X X X X X XXXXXXXXX-3′
5′- XXX XXXXXXXXXX XXX XXXXXXXXX-3′
5′- XX X X X X X X X X X X X X X X XXXXXXXXX-3′
5′- XX X X X X X X XXX X X XXX X X X X XX X XX-3′
5′- X XX X X X X X XXXXXX XX XX X XXXXXX-3′
5′- X XX X X X X X XXXXXX XX XX X XX X XXX-3′
5′- XX X X X X X X XXX X X X X X X XX XXX X XX-3′
5′-X X X X X X X X X X X X X X X X X X XXXXXXX-3′
5′-X X X X X X X X XXX X X X X X X XX XXX X XX-3′
5′- XX X X X XX XXXX X X X X X X XX XXX X XX-3′
5′- XX X X X X X X X X X X X X X X X X X X XXXXX-3′
5′- XX X X X X X X X X X X X X X X X X X X X X XXX-3′
5′- X XX X X X XXXXX X XX X XX X XXXX X XX-3′
5′-X X X X X XX XXXX X X X X X X XX XXX X XX-3′
5′- XX X X X XX XXXX X X X X X X XX XXXXXX-3′
5′-X XX X X X X XXX XX X X XX XX X X XXXXX-3′
5′-X X XX X X XX XX XX X X XX XX XXXX X XX-3′
5′-X XX X X X XX XX XX X X XX XX X X XX X XX-3′
5′-X X X XXX X X XXX X X X X X X X XXXXXXX-3′
5′-X X X X X X X X XXX X X X X XXX XXXXXXX-3′
5′-X X X XXX X X XXX X X X X XXX X X XXXXX-3′
5′-X X X XXXXX XX XX X X X XXX X X XX X XX-3′
5′-X X X X X X X X XXX X X X X X X X X XX XXXX-3′
5′- XXXXXXX XXXX X X X X X X XX XXX X XX-3′
5′- XXXXXXX XXXX X X X X X X X XXXX X XX-3′
5′-X X X XXX X X XXX X X X X XXX XXXXXXX-3′
5′-X XX X X X X XXX XX X X X XXXX XXXXXX-3′
5′-X XX X XXX XXX XXXX X XXX XXXXXXX-3′
5′-X X X XX X X XXX XX X XX X XX X X XXXXX-3′
5′- XX XX XXX XXX XX X X XX XXX XXXXXX-3′
5′-X X X XX X X XXX XX X XX X XXX XXXXXX-3′
5′-X X XX XXX XXX XX X XX X XX XXXX X XX-3′
5′-X XXX X XXX XXX X X X X X X XX XXXXXX-3′
“SM22” 5′-X X X X X X X X X X X X X X X X X X X X X X X XX -3′
5′-X X X X XXXXXXXXX X X X XXXXXXXXX-3′
5′-X X X X X XX XXXXX XX X X X XX XXX X XX-3′
5′-X X X X X X X X XX X X XX X X X X X X XX X XX-3′
5′- X XXXXXXXXXX X XXXXXXXXXXXXX-3′
5′-XX X XX X X X X X XXXXXX XX XXXXXXX-3′
5′-XXX X XX X X X XXX XX X X XX XX XXXXX-3′
5′-XXXXXXXXXXXXXXXXXX XXXX XXX-3′
5′-XXXXXXXXXXXXX XXXXX XXXXXXX-3′
5′-X X XX X XXXXXX X XX X XXXXXXXXXX-3′
5′-XX X X X XXXXXXX X X X XXXXXXXXXX-3′
5′-XX X XXXXX X XXX X XXXXX X XX X XXX-3′
5′-XXXXXXXXX X XXXXXXXXX X XX X XX-3′
5′- X XX X X X X X XXXXXX XX XXXXXXXXX-3′
5′-X X XX X X X XXX XX X X XX XX XXXXXXX-3′
and wherein said second strand comprises a modification pattern selected from the following:
AS-M1 3′- XXX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M2 3′- XXX X X X XX XXXX XX X X X X XXXXXXXX X -5′
AS-M3 3′- XXX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M4 3′- XXX X X X X XXXXXX X X X X X XXXXXXX XX -5′
AS-M5 3′- XXX X X XXXXXXXX X X X X X XXXXXXX XX -5′
AS-M6 3′- X X X XXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M7 3′- XX XXXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M8 3′- XXX X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M9 3′-XXX X X XX XXXX XX XX X XXXXXXXXXXX-5′
AS-M10 3′- XX X XX X X XXXXXXXXXX XX XXXX XXXX -5′
AS-M11 3′- X X X XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M12 3′- X X X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M13 3′- XX XX X XXXXXXXXXX X XXXXXXXXX XX -5′
AS-M14 3′- XX XX X XX XX XXXXXX X XXXXXXXXX XX -5′
AS-M15 3′- XX XXXXXXXXXXXXX X XXXXXXXXX XX -5′
AS-M16 3′- XX XX XX X X X X XXXXXXX XX XXXX XXXX -5′
AS-M17 3′- XXX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M18 3′- XX XX X XX X XXXXXXX X XXXXXXXXX XX -5′
AS-M19 3′- XXX X X X X X X X X X X X X X X XXXXXXXX XX -5′
AS-M20 3′- XXX X X X X X X X X X X X X X X XXXXXXXX X X-5′
AS-M21 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M22 3′- XXXX XXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M24 3′- XXX X X X X XXXXXXX XX X X XXXXXXX XX -5′
AS-M25 3′- XXX XXXXXXXXXXX XX X X XXXXXXX XX -5′
AS-M26 3′- XXX X X X X X X X X X X X X X X XXXXXXXXXX-5′
AS-M27 3′- XXX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M28 3′- XXX X X X X XXXXXXXXXXXXXXXXXXXX-5′
AS-M29 3′- XXX XXXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M30 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M31 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M32 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M34 3′- XXX X X X XXX XXX XX X X X X XXXXX XXXX -5′
AS-M35 3′- XXX X X X X X X XXXXX X X X XXXXXX XXXX -5′
AS-M36 3′- XXX X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M37 3′- XXX X X X X XXXXXXXXXXXXXXXXXX XX -5′
AS-M38 3′- XXX X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M40 3′- XXX XXXXXXXXXXXXXXXXXXXXXX XX -5′
AS-M41 3′- XXX X X X X XXXXXXX X X X XXXXXXXXXX-5′
AS-M42 3′- XX XX X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M43 3′- XXX X X XXXXXXXXX XX X X XXXXX XXXX -5′
AS-M44 3′- XXX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M45 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M46 3′- XXX X X X X X X X X X X X X X X X X X X X X X X X X -5′
AS-M47 3′- X X X X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M48 3′- XXX X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M52 3′- XXX X X X X X X X X X X X X X X X X X X X XXXXX -5′
AS-M54 3′- XXX X X XXXXXXXXX X X X X X XXXX XXXX -5′
AS-M55 3′- XXX X X XXXXXXX X X X X X XXXXXX XXXX -5′
AS-M56 3′- XXX X X X X XXXXXXX X X X X X XXXX XXXX -5′
AS-M57 3′- XXX X X X X XXXXX X X X X X XXXXXX XXXX -5′
AS-M58 3′- XXX X X XXXXXXX X X X X X X X XXXX XXXX -5′
AS-M59 3′- XXX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M60 3′- XXX X X X X XXXXXXX X X X XXXXX XXXXX -5′
AS-M61 3′- XXXXX XXXXXXXXX X X XXXX XXX XXXX -5′
AS-M62 3′- XXXXX XXXXXXXXX X X XXXX XXXX XXX -5′
AS-M63 3′- XXX X X X X X X XXXXX X X X X X XXXX XXXX -5′
AS-M64 3′- XXX X X X X X X XXX X X X X X X X XXXX XXXX -5′
AS-M65 3′- XXXXX XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M66 3′- XXXXXX XXXXXXXX X X X XXXXXX XXXX -5′
AS-M67 3′- XXX X X X XX XXXXXX X X X XXXXXX XXXX -5′
AS-M68 3′- XXX X X XXXXXXXX XXXX XXXXXX XXXX -5′
AS-M69 3′- XXX X X XXXXXXXX XXXXX XXXXX XXXX -5′
AS-M70 3′- XXXXX XXXXXXXXX XXX XXXXXX XXXX -5′
AS-M71 3′- XXX X X XXXXXXXX XX X XX XXXXX XXXX -5′
AS-M72 3′- XXX X X XXXXXXX X X X X X XX X XXX XXXX -5′
AS-M73 3′- XXX X XX XXXXXXXX X X XX XXXXX XXXX -5′
AS-M74 3′- XXX X X XXXXXXXX XX X X XXXXXX XXXX -5′
AS-M75 3′- XXX X X XXXXXXX X X XXX XXXXXX XXXX -5′
AS-M76 3′- XXX X X XXXXXXX X X XXXX X X XX XXXXX -5′
AS-M77 3′- XXX X X XXXXXXXXX XXXX XXXXX XXXX -5′
AS-M78 3′- XXX X X X X XXXXXXXX X X X XXXXX XXXX -5′
AS-M79 3′- XXX X X X XX XXXXXXXX XX XXXXX XXXX -5′
AS-M80 3′- XXX X X XXXXXXXXX XXX X X XXXX XXXX -5′
AS-M81 3′-XX X X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M82 3′- X p XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M83 3′- X p XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M84 3′- X X X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M85 3′-XXXX X XXXXXXXX X XXXXXXXXX XXXX -5′
AS-M88 3′-FFFX X X X X X X X X X X X X X XXXXXXFFFF-5′
AS-M89 3′- XXX XFX X XFXF X X X X X XXXXXXX XXXX -5′
AS-M90 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M91 3′-FFFX X X X XXXXX X X X X X X X XXXX XX FF-5′
AS-M92 3′- XXX X X XFXXXXXFXFX X X X XXXX XXXX -5′
AS-M93 3′-FFFXFX X XXXXX X X X X X XFXXXX XXXX -5′
AS-M94 3′-FFFXFXFXXXXXFXFXFXFXXXXFFFF-5′
AS-M95 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M96 3′-FFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′
AS-M210 3′- X X X X X X X X X X X X X X X X X X X X X XX XXXX -5′
AS-M1* 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M2* 3′-X XX X X X XX XXXX XX X X X X XXXXXXXX X -5′
AS-M3* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M4* 3′-X XX X X X X XXXXXX X X X X X XXXXXXX XX -5′
AS-M5* 3′-X XX X X XXXXXXXX X X X X X XXXXXXXX X -5′
AS-M6* 3′-XX X XXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M7* 3′-X X XXXXXXXXXXX X X X X X XXXXXXX XX -5′
AS-M8* 3′-X XX X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M9* 3′-XXX X X XX XXXX XX XX X XXXXXXXXXXX-5′
AS-M10* 3′-X X X XX X X XXXXXXXXXX XX XXXX XXXX -5′
AS-M11* 3′-XX X XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M12* 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M13* 3′-X X XX X XXXXXXXXXX X XXXXXXXXX XX -5′
AS-M14* 3′-X X XX X XX XX XXXXXX X XXXXXXXXX XX -5′
AS-M15* 3′-X X XXXXXXXXXXXXX X XXXXXXXXX XX -5′
AS-M16* 3′-X X XX XX X X X X XXXXXXX XX XXXX XXXX -5′
AS-M17* 3′-X XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M18* 3′-X X XX X XX X XXXXXXX X XXXXXXXXX XX -5′
AS-M19* 3′-X XX X X X X X X X X X X X X X X XXXXXXXX XX -5′
AS-M20* 3′-X XX X X X X X X X X X X X X X X XXXXXXXX X X-5′
AS-M21* 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M22* 3′-X XXX XXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M24* 3′-X XX X X X X XXXXXXX XX X X XXXXXXX XX -5′
AS-M25* 3′-X XX X X XXXXXXXXX XX X X XXXXXXX XX -5′
AS-M26* 3′-X XX X X X X X X X X X X X X X X XXXXXXXXXX-5′
AS-M27* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M28* 3′-X XX X X X X XXXXXXXXXXXXXXXXXXXX-5′
AS-M29* 3′-X XX XXXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M30* 3′-X XX X X X XX XXXX XX X X X X XXXXX XXXX -5′
AS-M31* 3′-X XX X X X X XXXXXXXXXXXXXXXX XXXX -5′
AS-M32* 3′-XX X X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M34* 3′-X XX X X X XXX XXX XX X X X X XXXXX XXXX -5′
AS-M35* 3′-X XX X X X X X X XXXXX X X X XXXXXX XXXX -5′
AS-M36* 3′-X XX X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M37* 3′-X XX X X X X XXXXXXXXXXXXXXXXXX XX -5′
AS-M38* 3′-X XX X X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M40* 3′-X XX XXXXXXXXXXXXXXXXXXXXXX XX -5′
AS-M41* 3′-X XX X X X X XXXXXXX X X X XXXXXXXXXX-5′
AS-M42* 3′-X X XX X XXXXXXXXXXXXXXXXXXXXXX-5′
AS-M43* 3′-X XX X X XXXXXXXXX XX X X XXXXX XXXX -5′
AS-M44* 3′-X XX XXXXXXXXXXX X X X XXXXXX XXXX -5′
AS-M45* 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M46* 3′-X XX X X X X X X X X X X X X X X X X X X X X X X X X -5′
AS-M47* 3′-X X X X XXXXXXXXXXXXXXXXXXXXXXX-5′
AS-M48* 3′-X XX X X XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M52* 3′-X XX X X X X X X X X X X X X X X X X X X X XXXXX -5′
AS-M54* 3′-X XX X X XXXXXXXXX X X X X X XXXX XXXX -5′
AS-M55* 3′-X XX X X XXXXXXX X X X X X XXXXXX XXXX -5′
AS-M56* 3′-X XX X X X X XXXXXXX X X X X X XXXX XXXX -5′
AS-M57* 3′-X XX X X X X XXXXX X X X X X XXXXXX XXXX -5′
AS-M58* 3′-X XX X X XXXXXXX X X X X X X X XXXX XXXX -5′
AS-M59* 3′-X XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M60* 3′-X XX X X X X XXXXXXX X X X XXXXX XXXXX -5′
AS-M61* 3′-X XXXX XXXXXXXXX X X XXXX XXX XXXX -5′
AS-M62* 3′-X XXXX XXXXXXXXX X X XXXX XXXX XXX -5′
AS-M63* 3′-X XX X X X X X X XXXXX X X X X X XXXX XXXX -5′
AS-M64* 3′-X XX X X X X X X XXX X X X X X X X XXXX XXXX -5′
AS-M65* 3′-X XXXX XXXXXXXXX X X X XXXXXX XXXX -5′
AS-M66* 3′-X XXXXX XXXXXXXX X X X XXXXXX XXXX -5′
AS-M67* 3′-X XX X X X XX XXXXXX X X X XXXXXX XXXX -5′
AS-M68* 3′-X XX X X XXXXXXXX XXXX XXXXXX XXXX -5′
AS-M69* 3′-X XX X X XXXXXXXX XXXXX XXXXX XXXX -5′
AS-M70* 3′-X XXXX XXXXXXXXX XXX XXXXXX XXXX -5′
AS-M71* 3′-X XX X X XXXXXXXX XX X XX XXXXX XXXX -5′
AS-M72* 3′-X XX X X XXXXXXX X X X X X XX X XXX XXXX -5′
AS-M73* 3′-X XX X XX XXXXXXXX X X XX XXXXX XXXX -5′
AS-M74* 3′-X XX X X XXXXXXXX XX X X XXXXXX XXXX -5′
AS-M75* 3′-X XX X X XXXXXXX X X XXX XXXXXX XXXX -5′
AS-M76* 3′-X XX X X XXXXXXX X X XXXX X X XX XXXXX -5′
AS-M77* 3′-X XX X X XXXXXXXXX XXXX XXXXX XXXX -5′
AS-M78* 3′-X XX X X X X XXXXXXXX X X X XXXXX XXXX -5′
AS-M79* 3′-X XX X X X XX XXXXXXXX XX XXXXX XXXX -5′
AS-M80* 3′-X XX X X XXXXXXXXX XXX X X XXXX XXXX -5′
AS-M81* 3′-XX X X X X X XXXXXXX X X X XXXXXX XXXX -5′
AS-M82* 3′-Xp XX X X X X X X X X X X X X X X XXXXXX XXXX -5′
AS-M83* 3′-Xp XX X X X X XXXXX X X X X X X X XXXX XXXX -5′
AS-M84* 3′-XX X X X X X X X X X X X X X X X X X XXXXXXXX-5′
AS-M85* 3′-XXXX X XXXXXXXX X XXXXXXXXX XXXX -5′
AS-M88* 3′-XFFX X X X X X X X X X X X X X XXXXXXFFFF-5′
AS-M89* 3′-X XX XFX X XFXFX X X X X X XXXXXX XXXX -5′
AS-M90* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M91* 3′-XFFX X X X XXXXX X X X X X X X XXXX XX FF-5′
AS-M92* 3′-X XX X X XFXXXXXFXFX X X X XXXX XXXX -5′
AS-M93* 3′-XFFXFX X XXXXX X X X X X XFXXXX XXXX -5′
AS-M94* 3′-XFFXFXFXXXXXFXFXFXFXXXXFFFF-5′
AS-M95* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′
AS-M96* 3′-XFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′
AS-M210* 3′-XX X X X X X X X X X X X X X X X X X X X XX XXXX -5′
wherein “X”=RNA “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA, and “p”=Phosphorothioate linkage.
84 . The method of claim 82 , wherein said dsNA is formulated in a lipid nanoparticle (LNP).
85 . The method of claim 82 , wherein said dsNA is administered at a dosage selected from the group consisting of 1 microgram to 5 milligrams per kilogram of said mammal per day, 100 micrograms to 0.5 milligrams per kilogram of said mammal per day, 0.001 to 0.25 milligrams per kilogram of said mammal per day, 0.01 to 20 micrograms per kilogram of said mammal per day, 0.01 to 10 micrograms per kilogram of said mammal per day, 0.10 to 5 micrograms per kilogram of said mammal per day, and 0.1 to 2.5 micrograms per kilogram of said mammal per day.
86 . The method of claim 82 , wherein α-1 antitrypsin mRNA levels are reduced in a tissue of said mammal by an amount (expressed by %) of at least 70% at least 3 days after said dsNA is administered to said mammal; wherein said tissue is liver tissue.
87 . The method of claim 82 , wherein said administering step comprises a mode selected from the group consisting of intravenous injection, intramuscular injection, intraperitoneal injection, infusion, subcutaneous injection, transdermal, aerosol, rectal, vaginal, topical, oral and inhaled delivery.
88 . The method of claim 82 , wherein the first strand is 36 nucleotides in length and the second strand is 22 nucleotides in length.Join the waitlist — get patent alerts
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