Sugar Modified Oligonucleotides and Uses Thereof
AssigneeIonis Pharmaceuticals, Inc.
InventorsMehran Nikan, Thazha P. Prakash, Eric E. Swayze
Life of this patent
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Abstract
The present disclosure provides RNAi agents comprising a stereo-non-standard nucleoside in the seed region thereof.
Claims197
An RNAi agent comprising an antisense RNAi oligomeric compound comprising an antisense RNAi oligonucleotide consisting of 20-25 linked nucleosides and a sense RNAi oligomeric compound comprising a sense RNAi oligonucleotide consisting of 15-23 linked nucleosides, wherein at least one nucleoside of the seed region of the antisense RNAi oligonucleotide is a one stereo non-standard nucleoside having Formula X:
- wherein one of J1 and J2 is H and the other is a heterocyclic base moiety Bx;
- one of J3 and J4 is H and the other is a 2′-substituent selected from H, OH, OMe, F, and OCH2CH2OCH3;
- one of J5 and J6 is H and the other is —O-5′ linkage:
- one of J7 and J8 is H and the other is —C(R1)2O-3′ linkage;
- wherein each R1 is independently H or C1-6 alkyl;
- provided that when J2 and J8 are both H, then one of J3 and J5 is not H:
- and provided that when Q is O and J2 is H, then J8 is not H;
- Q is O, S, or NR2;
- wherein R2 is H, C1-6 alkyl, acetyl, or methanesulfonyl;
- and
- Bx is a heterocyclic base moiety.
An RNAi agent for use in a method of comprising administering to a subject in need thereof a composition comprising the RNAi agent and a pharmaceutically acceptable carrier or diluent, optionally in a therapeutically effective amount thereof, wherein the RNAi agent comprises an antisense RNAi oligomeric compound comprising an antisense RNAi oligonucleotide consisting of 20-25 linked nucleosides and a sense RNAi oligomeric compound comprising a sense RNAi oligonucleotide consisting of 15-23 linked nucleosides, wherein at least one nucleoside of the seed region of the antisense RNAi oligonucleotide is a stereo non-standard nucleoside having Formula X:
- wherein one of J1 and J2 is H and the other is a heterocyclic base moiety Bx;
- one of J3 and J4 is H and the other is a 2′-substituent selected from H, OH, OMe, F, and OCH2CH2OCH3;
- one of J5 and J6 is H and the other is —O-5′ linkage to the remainder of the oligonucleotide;
- one of J7 and J8 is H and the other is —C(R1)2O-3′ linkage to the remainder of the oligonucleotide;
- wherein each R1 is independently H or C1-6 alkyl;
- provided that when Q is O and J2 and J8 are both H, then one of J3 and J5 is not H;
- Q is O, S, or NR2;
- and
- wherein R2 is H, C1-6 alkyl, or acetyl.
The RNAi agent of any of the preceding claims, wherein Q is O.
The RNAi agent of any of the preceding claims, wherein each R1 is H.
The RNAi agent of any of the preceding claims, wherein each R2 is H.
The RNAi agent of any of the preceding claims, wherein J2 and J7 are each H.
The RNAi agent of any of the preceding claims, wherein J6 is H.
The RNAi agent of any of the preceding claims, wherein Bx is selected from uracil, thymine, cytosine, 5-methyl cytosine, adenine, guanine, and hypoxanthine.
The RNAi agent of any of the preceding claims, wherein J3 and J4 are each H.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside has a structure selected from Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and Formula VII:
- wherein J3i,3ii, J3iii, J3iv, J3v, J3vi, and J3vii are as defined for J3 in Formula X;
- and J4i, J4ii, J4iii, J4iv, J4v, J4vi, and J4vii are as defined for J4 in Formula X;
- and Bx is a heterocyclic base moiety.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside has a structure of Formula I.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside has a structure of Formula VII.
The RNAi agent of any of the preceding claims, wherein exactly one nucleoside of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside.
The RNAi agent of any of the preceding claims, wherein 2, 3, 4, 5, or 6 nucleosides of the antisense RNAi oligonucleotide are stereo-non-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 6 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 3 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 4 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 5 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 7 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein nucleoside 8 from the 5′-terminus of the antisense RNAi oligonucleotide is a stereo-non-standard nucleoside, optionally wherein the remaining nucleosides in the antisense RNAi oligonucleotide are stereo-standard nucleosides.
The RNAi agent of any of the preceding claims, wherein each nucleoside in the sense RNAi oligonucleotide is a stereo-standard nucleoside.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside is linked on at least one of the 3′- or 5′-position with a phosphodiester, phosphorothioate, or mesyl phosphoramidate internucleoside linkage.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside is linked on at least one of the 3′- or 5′-position with a phosphodiester internucleoside linkage.
The RNAi agent of any of the preceding claims, wherein the stereo-non-standard nucleoside is linked at both the 3′- or 5′-positions with a phosphodiester internucleoside linkage.
The RNAi agent of any of the preceding claims, wherein each remaining nucleoside in the antisense RNAi oligonucleotide is independently selected from:
- a bicyclic nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-MOE nucleoside, a 2′-NMA nucleoside, a 2′-deoxynucleoside, and a ribosyl nucleoside.
The RNAi agent of any of the preceding claims, wherein each remaining nucleoside in the antisense RNAi oligonucleotide is a stereo-standard nucleoside independently selected from:
- a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-MOE nucleoside, and a 2′-deoxynucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the antisense RNAi oligonucleotide is a 2′-OMe nucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, or three of the nucleosides at positions 3, 4, and 5 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein each of the nucleosides at positions 3, 4, 5 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein one, two, three, four, or five of the nucleosides at positions 7, 8, 9, 10, and 11 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein each of the nucleosides at positions 7, 8, 9, 10, and 11 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein one, two, three, four, or five of the nucleosides at positions 17, 18, 19, 20, and 21 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein each of the nucleosides at positions 17, 18, 19, 20, and 21 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-OMe nucleosides.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the antisense RNAi oligonucleotide is a 2′-F nucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, or three of the nucleosides at positions 2, 14, and 16 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-F nucleosides.
The RNAi agent of any of the preceding claims, wherein each of the nucleosides at positions 2, 14, and 16 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-F nucleosides.
The RNAi agent of any of the preceding claims, wherein the nucleoside at position 6 from the 5′-terminus of the antisense RNAi oligonucleotide is a 2′-F nucleoside.
The RNAi agent of any of the preceding claims, wherein the nucleoside at position 6 from the 5′-terminus of the antisense RNAi oligonucleotide is a 2′-OMe nucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the antisense RNAi oligonucleotide is a 2′-MOE nucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, three, four, or five of the nucleosides at positions 1 from the 5′-terminus of the antisense RNAi oligonucleotide and positions 1, 2, 3, 4, or 5 from the 3′-terminus of the antisense RNAi oligonucleotide are 2′-MOE nucleosides:
- optionally wherein the antisense RNAi oligonucleotide consists of 23 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the nucleoside at position 1 from the 5′-terminus of the antisense RNAi oligonucleotide is a 2′-MOE nucleoside.
The RNAi agent of any of the preceding claims, wherein each of the nucleosides at positions 1 from the 5′-terminus of the antisense RNAi oligonucleotide and positions 1 and 2 from the 3′-end of the antisense RNAi oligonucleotide are 2′-MOE nucleosides.
The RNAi agent of any of the preceding claims, wherein one or two of the nucleosides at positions 9 and 10 from the 5′-terminus of the antisense RNAi oligonucleotide are 2′-MOE nucleosides.
The RNAi agent of any of the preceding claims, wherein the 5′-terminal nucleoside of the antisense RNAi oligonucleotide comprises a stabilized phosphate group.
The RNAi agent of any of the preceding claims, wherein the antisense RNAi oligonucleotide consists of 21-23, optionally 23, linked nucleosides.
The RNAi agent of any of the preceding claims, wherein each nucleoside in the sense RNAi oligonucleotide is independently selected from:
- a bicyclic nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a 2′-MOE nucleoside, a 2′-NMA nucleoside, a 2′-deoxynucleoside, and a ribosyl nucleoside.
The RNAi agent of any of the preceding claims, wherein each nucleoside in the sense RNAi oligonucleotide is a stereo-standard nucleoside independently selected from:
- a 2′-OMc nucleoside, a 2′-F nucleoside, a 2′-MOE nucleoside, and a 2′-deoxynucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the sense RNAi oligonucleotide is a 2′-OMe nucleoside.
The RNAi agent of any of the preceding claims, wherein at least one of the nucleosides at positions 3-6 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-OMe nucleosides, optionally wherein each of the nucleosides at positions 3-8 is a 2′-OMe nucleoside.
The RNAi agent of any of the preceding claims, wherein at least one of the nucleosides at positions 12-19 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-OMe nucleosides, optionally wherein each of the nucleosides at positions 12-19 is a 2′-OMe nucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the sense RNAi oligonucleotide is a 2′-F nucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, three, or four of the nucleosides at positions 7 and 9-11 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-F nucleosides, optionally wherein each of the nucleosides at positions 7 and 9-11 is a 2′-F nucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the sense RNAi oligonucleotide is a 2′-deoxynucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, three, four, or five of the nucleosides at positions 7-11 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-deoxynucleosides, optionally wherein one of the nucleosides at positions 7-11 is a 2′-deoxynucleoside.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the sense RNAi oligonucleotide is a 2′-MOE nucleoside.
The RNAi agent of any of the preceding claims, wherein one, two, three, or four of the nucleosides at positions 1, 2, 20, and 21 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-MOE nucleosides, optionally wherein each of positions 1, 2, 20, and 21 is a 2′-MOE nucleoside;
- optionally wherein the sense RNAi oligonucleotide consists of 21 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein one, two, three, or four of the nucleosides at positions 1, 2, 18, 19 from the 5′-terminus of the sense RNAi oligonucleotide are 2′-MOE nucleosides, optionally wherein each of positions 1, 2, 18, and 19 is a 2′-MOE nucleoside:
- optionally wherein the sense RNAi oligonucleotide consists of 19 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein at least one nucleoside in the sense RNAi oligonucleotide is substituted at its 2′-position with a C16-C22 alkyl group, optionally wherein the C16-C22 alkyl group is unsubstituted, optionally wherein the C16-C22 alkyl group is saturated.
The RNAi agent of any of the preceding claims, wherein the sense RNAi oligonucleotide consists of 14-21 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the sense RNAi oligonucleotide consists of 19-21, optionally 21, linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the antisense RNAi oligonucleotide comprises one, two, three, or four phosphorothioate internucleoside linkages joining nucleosides at positions selected from 1 and 2, 2 and 3 from the 5′-terminus thereof, and positions 1 and 2, 2 and 3 from the 3′-terminus thereof.
The RNAi agent of any of the preceding claims, wherein the sense RNAi oligonucleotide comprises one, two, three, or four phosphorothioate internucleoside linkages joining nucleosides at positions selected from 1 and 2, 2 and 3 from the 5′-terminus thereof, and positions 1 and 2, 2 and 3 from the 3′-terminus thereof.
The RNAi agent of any of the preceding claims, wherein the antisense RNAi oligonucleotide comprises an overhang of two nucleosides at the 3′-terminus thereof.
The RNAi agent of any of the preceding claims, wherein each overhanging nucleoside comprises a 2′-MOE sugar moiety or a 2′-deoxy sugar moiety.
The RNAi agent of any of the preceding claims, wherein the antisense siRNA oligonucleotide has a nucleobase sequence comprising a targeting region comprising at least 15, optionally 15-21, contiguous nucleobases, wherein the nucleobase sequence of targeting region is at least 85% complementary to an equal length portion of the nucleobase sequence of a target RNA.
The RNAi agent of any of the preceding claims, wherein the sense siRNA oligonucleotide is sufficiently complementary to the antisense siRNA oligonucleotide to fonn a stable duplex at room temperature in water.
The RNAi agent of any of the preceding claims, wherein the antisense RNAi oligonucleotide consists of 21 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the antisense RNAi oligonucleotide consists of 23 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the sense RNAi oligonucleotide consists of 19 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the sense RNAi oligonucleotide consists of 21 linked nucleosides.
The RNAi agent of any of the preceding claims, wherein the RNAi agent comprises a conjugate group.
An RNAi agent comprising an antisense RNAi oligomeric compound comprising an antisense RNAi oligonucleotide consisting of 20-50 linked nucleosides and optionally a sense RNAi oligomeric compound comprising a sense RNAi oligonucleotide consisting of 15-23 linked nucleosides, wherein the antisense RNAi oligonucleotide comprises at one or more of nucleosides 3-8 from the 5′-terminus thereof a nucleoside having Formula I:
- wherein J3i is H and J4i is selected from H, OH, OMe, F, and OCH2CH2OCH3;
- and Bx is a heterocyclic base moiety;
- provided that the RNAi agent does not comprise any of the following:
- wherein “VP” represents a 5′-vinyl phosphonate moiety, “p” represents a 5′-phosphate moiety, a subscript “[f2bDx]” represents a 2′-fluoro-β-D-xylosyl sugar moiety, a subscript “f” represents a 2′-fluoro-β-D-ribosyl sugar moiety, a subscript “y” represents a 2′-O-methyl-β-D-ribosyl sugar moiety, a subscript “e” represents a 2′-MOE-β-D-ribosyl sugar moiety, a superscript “m” represents a 5-methyl group on cytosine, a subscript “s” represents a phosphorothioate internucleoside linkage, and a subscript “o” represents a phosphodiester internucleoside linkage.
A population of RNAi agents of any of the preceding claims, wherein the stereo-non-standard nucleoside is chirally enriched for internucleoside linkages having the Rp or Sp configuration.
Dependencies are inferred from the claim text.