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1. WO2015017675 - PROCÉDÉS ET COMPOSÉS UTILES DANS DES PATHOLOGIES ASSOCIÉES À UN NOMBRE PLUS GRAND DE RÉPÉTITIONS

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

CLAIMS:

1. A compound comprising a single-stranded oligonucleotide consisting of 13 to 30 linked nucleosides and having a nucleobase sequence complementary to a repeat region of an expanded repeat-containing target RNA, wherein the 5'-terminal nucleoside of the single-stranded oligonucleotide comprises a phosphate moiety and an intereucleoside linking group linking the 5'-terminal nucleoside to the remainder of the oligonucleotide.

2. The compound of claim 1, wherein the 5'-terminal nucleoside of the single-stranded oligonucleotide has

Formula I:


wherein:

T1 is a phosphorus moiety;

T2 is an internucleoside linking group linking the 5'-terminal nucleoside of Formula I to the remainder of the oligonucleotide;

A has a formula selected from among:


Q1 and Q2 are each independently selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, and N(R3)(R4);

Q3 is selected from among: O, S, N(R5), and C(R6)(R7);

each R3, R4 R5, R6 and R7 is independently selected from among: H, C1-C6 alkyl, substituted C1-C6 alkyl, and C1-C6 alkoxy;

M3 is selected from among: O, S, NR14, C(R14)(R16), C(R14)(R16)C(R17)(R18), C(R14)=C(R17), OC(R14)(R16), and OC(R14)(Bx2);

R14 is selected from among: H, C1-C6 s fddddv bffdfsdfdfs dfsdf sdfsl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, and substituted C2-C6 alkynyl;

R14, R16, R17 and R18 are each independently selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, and substituted C2-C6 alkynyl;

if Bx2 is present, then Bx2 is a nucleobase and Bx1 is selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, and substituted C2-C6 alkynyl;

if Bx2 is not present, then Bx1 is a nucleobase;

either each of J4, J5, Je and J7 is independently selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, and substituted C2-C6 alkynyl;

or J4 forms a bridge with one of J5 or J7 wherein the bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR19, C(R20)(R21), C(R20)=C(R21), C[=C(R20)(R21)] and C(=O) and the other two of J5, Je and J7 are independently selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, d-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, and substituted C2-C6 alkynyl;

each R1g, R20 and R21 is independently selected from among: H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;

G is selected from among: H, OH, halogen, O-[C(R8)(R9)]n-[(C=O)m-X1]j-Z, and a conjugate group;

each R8 and R9 is independently selected from among: H, halogen, C1-C6 alkyl, and substituted C1-C6 alkyl;

X1 is O, S or N(E1);

Z is selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, and N(E2)(E3);

E1, E2 and E3 are each independently selected from among: H, C1-C6 alkyl, and substituted C1-C6 alkyl;

n is from 1 to 6;

m is 0 or 1;

j is 0 or 1;

provided that, if j is 1 , then Z is other than halogen or N(E2)(E3);

each substituted group comprises one or more optionally protected substituent groups independently selected from among: a halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=X2)J1, OC(=X2)N(J1)(J2), and C(=X2)N(J1)(J2);

X2 is O, S or NJ3; and

each J1, J2 and J3 is independently selected from among: H and C1-C6 alkyl.

3. The compound of claim 2, wherein M3 is selected from among: O, CH=CH, OCH2, and OC(H)(Bx2).

4. The compound of claim 2, wherein M3 is O.

5. The compound of any of claims 2-4, wherein each of J4, J5, J6 and J7 is H.

6. The compound of any of claims 2-5, wherein J4 forms a bridge with either J5 or J7.

7. The compound of any of claims 2-6, wherein A has the formula:


wherein:

Q1 and Q2 are each independently selected from among: H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy.

8. The compound of claim 7, wherein each of Q1 and Q2 is H.

9. The compound of claim 7, wherein Q1 and Q2 are each independently selected from among: H and a halogen.

10. The compound of claim 7, wherein one of Q1 and Q2 is H and the other of Q1 and Q2 is F, CH3 or OCH3.

11. The compound of any of claims 2 to 10, wherein T1 has the formula:


wherein:

Ra and Rc are each independently selected from among: protected hydroxyl, protected thiol, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, protected amino or substituted amino; and

Rb is O or S.

12. The compound of claim 11, wherein Rb is O and Ra and Rc are each, independently selected from among OCH3, OCH2CH3, OCH(CH3)2.

13. The compound of any of claims 2 to 12, wherein G is selected from among: a halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2): SCH3, O(CH2)2-OCF3, O(CH2)3-N(R10)(R11), O(CH2)2-ON(R10)(R11), O(CH2)2-O(CH2)2-N(R10)(R11), OCH2C(=O)-N(R10)(R11), OCH2C(=O)-N(R12)-(CH2)2-N(R10)(R11), and O(CH2)2-N(R12)- C(=NR13)[N(R10)(R11)]; wherein R10, R11, R12 and Ri3 are each, independently, H or C1-C6 alkyl.

14. The compound of any of claims 2-13, wherein G is selected from among: a halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)- N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, and OCH2-N(H)-C(=NH)NH2.

15. The compound of any of claims 2-14, wherein G is selected from among: F, OCH3, and O(CH2)2-OCH3.

16. The compound of claim 15, wherein G is O(CH2)2-OCH3.

17. The compound of any of claims 2-13, wherein G is a conjugate group.

18. The compound of clam 17, wherein the conjugate of the conjugate group is selected from among: an intercalator, a polyamine, a polyamide, a polyethylene glycol, a thioether, a polyether, a cholesterol, a thiocholesterol, a cholic acid moiety, a folate, a lipid, a phospholipid, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, a fluorescein, a rhodamine, and a coumarin.

19. The compound of claims 17 or 18, wherein the conjugate of the conjugate group is selected from among: cholesterol, palmityl, stearoyl, lithocholic-oleyl, C22 alkyl, C20 alkyl, C16 alkyl, C18 alkyl, and C10 alkyl.

20. The compound of any of claims 17-19, wherein the conjugate group comprises a linker.

21. The compound of claim 20, wherein the linker is selected from among: hexanamide, 8-amino-3,6- dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-l-carboxylate (SMCC), 6- aminohexanoic acid (AHEX or AHA), substituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, and substituted or unsubstituted C2-C10 alkynyl.

22. The compound of any of claims 2-21, wherein the nucleobase is a modified nucleobase.

23. The compound of any of claims 2-22, wherein the nucleobase is a pyrimidine, substituted pyrimidine, purine or substituted purine.

24. The compound of any of claims 2-23, wherein the nucleobase is uracil, thymine, cytosine, 5- methylcytosine, adenine or guanine.

25. The compound of any of claims 2-24, wherein the 5'-terminal nucleoside of the single-stranded

oligonucleotide has Formula III:


26. The compound of claim 25, wherein A has the formula:


wherein Q1 and Q2 are each independently selected from among: H, a halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, and substituted C1-C6 alkoxy.

27. The compound of claim 26, wherein Q1 and Q2 are each independently selected from among: H, F, CH3, and OCH3.

28. The compound of any of claims 2-27, wherein the 5'-terminal nucleoside has Formula V:


wherein:

Bx is selected from among: uracil, thymine, cytosine, 5-methyl cytosine, adenine, and guanine;

T2 is a phosphorothioate internucleoside linking group linking the compound of Formula V to the remainder of the oligonucleotide; and

G is selected from among: a halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2-CH=CH2, O(CH2)2-OCH3, O(CH2)2-O(CH2)2-N(CH3)2, OCH2C(=O)-N(H)CH3, OCH2C(=O)-N(H)-(CH2)2-N(CH3)2, OCH2-N(H)-C(=NH)NH2, and a conjugate group.

29. The compound of any of claims 1-28, wherein the remainder of the oligonucleotide comprises at least one RNA or RNA-like nucleoside.

30. The compound of claim 29, wherein essentially each nucleoside of the remainder of the oligonucleotide is an RNA-like nucleoside.

31. The compound of claim 30, wherein each nucleoside of the remainder of the oligonucleotide is an RNA or RNA-like nucleoside.

32. The compound of any of claims 29-31, wherein each RNA-like nucleoside is independently selected from among: a 2'-endo furanosyl nucleoside and an RNA-surrogate nucleoside.

33. The compound of claim 32, wherein each RNA-like nucleoside is a 2'-endo furanosyl nucleoside.

34. The compound of claim 33, wherein each RNA-like nucleoside is selected from among: 2'-F, 2'-MOE, 2'-OMe, LNA, F-HNA, and cEt.

35. The compound of any of claims 1-34, wherein the remainder of the oligonucleotide comprises at least one region having sugar motif:

-[(A)x-(B)y-(A)z]q- wherein

A is a modified nucleoside of a first type,

B is a modified nucleoside of a second type;

each x and each y is independently 1 or 2;

z is 0 or 1;

q is 1-15;

36. The compound of claim 35, wherein the modifications of the first type and the modifications of the second type are selected from among: 2'-F, 2'-OMe, and F-HNA.

37. The compound of claim 35, wherein the modifications of the first type are 2'-F and the modifications of the second type are 2'-OMe.

38. The compound of claim 35, wherein the modifications of the first type are 2'-OMe and the modifications of the second type are 2'-F.

39. The compound of any of claims 35-38, wherein each x and each y is 1.

40. The compound of any of claims 1-39, wherein the remainder of the oligonucleotide comprises 1-4

3 'terminal nucleosides, each comprising the same sugar modification, wherein the sugar modification of the 1-4 3 'terminal nucleosides is different from the sugar modification of the immediately adjacent nucleoside.

41. The compound of claim 40, wherein the 3'-terminal nucleosides are each 2'-MOE nucleosides.

42. The compound of claim 40 or 41 comprising two 3'-terminal nucleosides.

43. The compound of any of claims 1-42, comprising at least one modified internucleoside linkage.

44. The compound of claim 43, wherein each mternucleoside linkage is selected from phosphorothioate and phosphodiester.

45. The compound of claim 43 or 44, wherein each of the 6-10 3'-most mternucleoside linkages is

phosphorothioate linkage.

46. The compound of any of claims 43-45, wherein the 5'-most mternucleoside linkage is a phosphorothioate linkage.

47. The compound of any of claims 43-46, comprising a region of alternating linkages.

48. The compound of any of claims 1-47, comprising a 5'region having the motif:

(Nucleoside of Formula I, III, or V)-s-(A-s-B-o-A)x(-s-B)Y

wherein:

A is a nucleoside of a first type;

B is a nucleoside of a second type;

s is a phosphorothioate linkage;

o is a phosphodiester linkage;

X is 1-8; and

Y is 1 or 0.

49. The compound of any of claims 1-48, comprising a 3 'region having the motif:

-(A-s-B-s-A)z(-s-B)q-s-(D)-(s-D)r

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type;

D is a nucleoside of a third type;

Z is 1-5;

q is 1 or 0; and

and r is 0-3.

50. The compound claim 48 or 49, wherein A is a 2'-F nucleoside.

51. The compound of any of claims 48-50, wherein B is a 2'-OMe nucleoside.

52. The compound of any of claims 49-51, wherein D is a 2'-MOE nucleoside.

53. The compound of any of claims 49-52, wherein the oligonucleotide comprises a hybridizing region and a 3'-terminal region, wherein the hybridizing region comprisies nucleosides A and B and the terminal region comprising nucleosides D, wherein the hybridizing region is complementary to the repeat region of the expanded repeat-containing target RNA.

54. The compound of any of claims 1-48, comprising the motif:

(Nucleoside of Formula V)-s-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-s-A-s-B-s- A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

55. The compound of any of claims 1-48, consisting of the motif:

(Nucleoside of Formula V)-s-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-s-A-s-B-s- A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

56. The compound of any of claims 1-48, consisting of the motif:

(Nucleoside of Formula V)-s-C-o-C-o-C-o-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-s-A-s-B-s- A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

57. The compound of any of claims 1-48, consisting of the motif:

(Nucleoside of Formula V)-s-A-o-B-o-A-o-C-o-C-o-C-o-A-s-B-o-A-s-B-o-A-s-B-o-A-s-B-s-A-s-B- s-A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

58. The compound of any of claims 1-48, consisting of the motif:

(Nucleoside of Formula V)-s-A-s-B-o-A-s-B-o-A-s-B-o-C-o-C-o-C-o-B-o-A-s-B-o-A-s-B-s-A-s-B-s- A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

59. The compound of any of claims 1-48, consisting of the motif:

(Nucleoside of Formula V)-s- C-o-C-o-C-o- C-o-C-o-C-o- C-o-C-o-C-o-B-o-A-s-B-o-A-s-B-s-A-s- B-s-A-s-B-s-D-s-D-s

wherein:

s is a phosphorothioate linkage;

A is a nucleoside of a first type;

B is a nucleoside of a second type; and

D is a nucleoside of a third type.

60. The compound of claim 54 to 59, wherein A is a 2'-F nucleoside.

61. The compound of any of claims 54-60, wherein B is a 2'-OMe nucleoside.

62. The compound of any of claims 54-61, wherein D is a 2'-MOE nucleoside.

63. The compound of any of claims 54-61, wherein C is a ribonucleoside.

64. The compound of any of claims 1-63, wherein the remainder of the oligonucleotide comprises at least one conjugate group.

65. The compound of claim 64, wherein the conjugate of the conjugate group is selected from among: an intercalator, a polyamine, a polyamide, a polyethylene glycol, a thioether, a polyether, a cholesterol, a thiocholesterol, a cholic acid moiety, a folate, a lipid, a phospholipid, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, a fluorescein, a rhodamine, and a coumarin.

66. The compound of claims 64 or 65, wherein the conjugate of the conjugate group is selected from among: cholesterol, palmityl, stearoyl, lithocholic-oleyl, C22 alkyl, C20 alkyl, C16 alkyl, C18 alkyl, and C10 alkyl.

67. The compound of any of claims 64-66, wherein the conjugate group comprises a linker.

68. The compound of claim 67, wherein the linker is selected from among: hexanamide, 8-amino-3,6- dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-l-carboxylate (SMCC), 6- aminohexanoic acid (AHEX or AHA), substituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, and substituted or unsubstituted C2-C10 alkynyl.

69. The compound of any of claims 1-68, wherein the oligonucleotide is 100% complementary to the repeat region of the expanded repeat-containing target RNA.

70. The compound of any of claims 1-68, wherein the oligonucleotide has one mismatch relative to the repeat region of the expanded repeat-containing target RNA.

71. The compound of any of claims 1-68, wherein the oligonucleotide has two mismatches relative to the repeat region of the expanded repeat-containing target RNA.

72. The compound of any of claims 1-68, wherein the oligonucleotide has three mismatches relative to the repeat region of the expanded repeat-containing target RNA.

73. The compound of any of claims 1-68, wherein the oligonucleotide has four mismatches relative to the repeat region of the expanded repeat-containing target RNA.

74. The compound of any of claims 1-68, wherein the oligonucleotide has five mismatches relative to the repeat region of the expanded repeat-containing target RNA.

75. The compound of any of claims 1-74, wherein the oligonucleotide comprises a hybridizing region and 0- 4 3 -terminal nucleosides.

76. The compound of any of claims 1-74, wherein the oligonucleotide comprises a hybridizing region and 1- 4 3'-terminal nucleosides.

77. The compound of claim 75 or 76, wherein the hybridizing region is 100% complementary to the repeat region of the expanded repeat-containing target RNA.

78. The compound of claim 75 or 76, wherein the hybridizing region has one mismatch relative to the repeat region of the expanded repeat-containing target RNA.

79. The compound of claim 75 or 76, wherein the hybridizing region has two mismatches relative to the repeat region of the expanded repeat-containing target RNA.

80. The compound of claim 75 or 76 wherein the hybridizing region has three mismatches relative to the repeat region of the expanded repeat-containing target RNA.

81. The compound of claim 75 or 76 wherein the hybridizing region has four mismatches relative to the repeat region of the expanded repeat-containing target RNA.

82. The compound of claim 75 or 76 wherein the hybridizing region has five mismatches relative to the repeat region of the expanded repeat-containing target RNA.

83. The compound of any of claims 70-82, having a mismatch at the eighth nucleobase from the 5'-end of the hybridizing region.

84. The compound of any of claims 70-83, having a mismatch at the ninth nucleobase from the 5'-end of the hybridizing region.

85. The compound of any of claims 70-84, having a mismatch at the tenth nucleobase from the 5'-end of the hybridizing region.

86. The compound of any of claims 70-85, having a mismatch at the ninth nucleobase from the 3 '-end of the hybridizing region.

87. The compound of any of claims 70-86, having a mismatch at the tenth nucleobase from the 3 '-end of the hybridizing region.

88. The compound of any of claims 70-87, having a mismatch at the eleventh nucleobase from the 3'-end of the hybridizing region.

89. The compound of any of claims 1-68, wherein the oligonucleotide comprises a hybridizing region having two or more mismatches relative to the repeat region of the expanded repeat-containing target RNA, and wherein each of the mismatches is adjacent to one another.

90. The compound of any of claims 1-68, wherein the oligonucleotide comprises a hybridizing region having three or more mismatches relative to the repeat region of the expanded repeat-containing target RNA, and wherein each of the mismatches is adjacent to one another.

91. The compound of any of claims 1-68, wherein the oligonucleotide comprises a hybridizing region having two mismatches relative to the repeat region of the expanded repeat-containing target RNA, and wherein each of the mismatches is adjacent to one another.

92. The compound of claim 86, wherein the mismatches are located at the 9th and 10th nucleobases from the 5'-terminal nucleoside of the compound.

93. The compound of claim 86, wherein the mismatches are located at the 10th and 11th nucleobases from the 5'-terminal nucleoside of the compound.

94. The compound of claim 86, wherein the mismatches are located at the 8th and 9th nucleobases from the 5'- terminal nucleoside of the compound.

95. The compound of any of claims 1-68, wherein the oligonucleotide comprises a hybridizing region having three mismatches relative to the repeat region of the expanded repeat-containing target RNA, and wherein each of the mismatches is adjacent to one another.

96. The compound of claim 95, wherein the mismatches are located at the 9th, 10th, and 11th nucleobases from the 5'-terminal nucleoside of the compound.

97. The compound of claim 95, wherein the mismatches are located at the 10th, 11th and 12th nucleobases from the 5'-terminal nucleoside of the compound.

98. The compound of claim 95, wherein the mismatches are located at the 8th, 9th, and 10th nucleobases from the 5'-terminal nucleoside of the compound.

99. The compound of any of claims 1-68, wherein the oligonucleotide comprises a hybridizing region having four mismatches relative to the repeat region of the expanded repeat-containing target RNA, and wherein each of the mismatches is adjacent to one another.

100. The compound of claim 99, wherein the mismatches are located at the 8th, 9th, 10th, and 11th

nucleobases from the 5'-terminal nucleoside of the compound.

101. The compound of claim 99, wherein the mismatches are located at the 9th, 10th, 11th and 12th

nucleobases from the 5'-terminal nucleoside of the compound.

102. The compound of claim 99, wherein the mismatches are located at the 7th, 8th, 9th, and 10th

nucleobases from the 5'-terminal nucleoside of the compound.

103. The compound of any of claims 1-68, having a mismatch at ninth and 10th nucleobase from the 5'- terminal nucleoside of the compound.

104. The compound of any of claims 1-68, having a mismatch at ninth and 11th nucleobase from the 5'- terminal nucleoside of the compound.

105. The compound of any of claims 1-68, having a mismatch at ninth and 12th nucleobase from the 5'- terminal nucleoside of the compound.

106. The compound of any of claims 1-68, having a mismatch at ninth and 13th nucleobase from the 5'- terminal nucleoside of the compound.

107. The compound of any of claims 1-68, having a mismatch at ninth and 14th nucleobase from the 5'- terminal nucleoside of the compound.

108. The compound of any of claims 1-68, having a mismatch at ninth and 15th nucleobase from the 5'- terminal nucleoside of the compound.

109. The compound of any of claims 1 -68, having a mismatch at ninth and 16 nucleobase from the 5'- terminal nucleoside of the compound.

110. The compound of any of claims 1-68, having a mismatch at ninth and 17th nucleobase from the 5'- terminal nucleoside of the compound.

111. The compound of any of claims 1-68, having a mismatch at ninth and 18th nucleobase from the 5'- terminal nucleoside of the compound.

112. The compound of any of claims 1-68, having a mismatch at ninth, 10th, and 11th nucleobase from the 5'-terminal nucleoside of the compound.

113. The compound of any of claims 1-68, having a mismatch at 8th, 9th, 10th, and 11th nucleobase from the 5'-terminal nucleoside of the compound.

114. The compound of any of claims 1-68, having a mismatch at 4th, 10th, and 11th nucleobase from the 5'-terminal nucleoside of the compound.

115. The compound of any of claims 1-68, having a mismatch at 3rd, 8th, 13th, and 17th nucleobase from the 5'-terminal nucleoside of the compound.

116. The compound of any of claims 69-115, wherein one or more of the 3 '-terminal nucleosides is not complementary to the target RNA.

117. The compound of any of claims 69-116, wherein the nucleobase of each 3'-terminal nucleoside is a purine.

118. The compound of claim 117, wherein the nucleobase of each 3 '-terminal nucleoside is an adenine.

119. The compound of any of claims 1-118, wherein the repeat region of the expanded repeat-containing RNA consists of a repeating triplet.

120. The compound of claim 119, wherein the repeating triplet is CAG.

121. The compound of claim 119, wherein the repeating triplet is CUG.

122. The compound of any of claims 1-121 wherein the expanded repeat-containing RNA is associated with spinocerebellar ataxia.

123. The compound of any of claims 1-121 wherein the expanded repeat-containing RNA is associated with spinocerebellar ataxia 3.

124. The compound of any of claims 1-121 wherein the expanded repeat-containing RNA is associated with spinocerebellar ataxia 10.

125. The compound of any of claims 1-121 wherein the expanded repeat-containing RNA is associated with Dentatorubral-pallidoluysian atrophy.

126. The compound of any of claims 1-125, wherein the compound is a mutant selective compound.

127. The compound of claim 126, wherein the compound is capable of reducing the activity or amount of an expanded repeat-containing RNA at least ten fold more than it reduces the activity or amount of a corresponding wild type RNA.

128. The compound of claim 126 or 127, wherein the compound is capable of reducing the activity or amount of a protein encoded by an expanded repeat-containing RNA at least ten fold more than it reduces the activity or amount of a corresponding wild type protein.

129. The compound of claim 126, wherein the compound is capable of reducing the activity or amount of an expanded repeat-containing RNA at least five fold more than it reduces the activity or amount of a corresponding wild type RNA.

130. The compound of claim 126 or 127, wherein the compound is capable of reducing the activity or amount of a protein encoded by an expanded repeat-containing RNA at least five fold more than it reduces the activity or amount of a corresponding wild type protein.

131. The compound of claim 126 or 127, wherein the compound is capable of distribution throughout the ipsilateral striatum, contralateral cortex, contralateral striatum, thalamus, cerebellum, and brainstem.

132. The compound of claim 125 or 126, wherein a single dose of the compound is capable of reducing the activity or amount of mutant ATXN-3 expression for up to 5 days.

133. The compound of claim 125 or 126, wherein a single dose of the compound is capable of reducing the activity or amount of mutant ATXN-3 expression for up to 8 days.

134. The compound of any of 1-133, wherein the oligonucleotide comprises at least one modified nucleobase.

135. A method of selectively reducing the activity or amount of an expanded repeat-containing RNA in a cell, comprising contacting a cell having an expanded repeat-containing RNA with at least one compound of any of claims 1 to 134; and thereby selectively reducing the activity or amount of the expanded repeat- containing RNA in the cell.

136. The method of claim 135, wherein the amount or activity of the expanded repeat-containing RNA is reduced at least ten-fold more than that of a corresponding wild-type RNA.

137. The method of claim 134 or 135, wherein the cell is in vitro.

138. The method of claim 134 or 135, wherein the cell is in an animal.

139. The method of claim 134 or 135, wherein the expanded repeat-containing RNA is ATXN-3 RNA.

140. A method of selectively reducing the amount or activity of a protein encoded by an expanded repeat- containing RNA in a cell, comprising contacting a cell having an expanded repeat-containing RNA with at least one compound of any of claims 1 to 134; and thereby selectively reducing the activity or amount of the protein encoded by the expanded repeat-containing RNA in the cell.

141. The method of claim 139, wherein the amount or activity of the protein encoded by the expanded repeat-containing RNA is reduced at least ten-fold more than that of a corresponding wild-type protein.

142. The method of claim 139 or 140, wherein the cell is in vitro.

143. The method of claim 139 or 140, wherein the cell is in an animal.

144. The method of claim 134 or 135, wherein the protein encoded by an expanded repeat-containing RNA is ATXN-3.

145. The method of claim 134 or 135, wherein the protein encoded by an expanded repeat-containing RNA is ATN-1.

146. A pharmaceutical composition comprising at least one compound of any of claims 1-133 and a pharmaceutical carrier or diluents.

147. A method of treating a patient having a disease associated with an expanded repeat-containing RNA comprising administering to the patient the pharmaceutical composition of claim 146.

148. The method of claim 147, wherein the disease is selected from among: spinocerebellar ataxia 10 or spinocerebellar ataxia 3.

149. The method of claim 147, wherein the disease is Dentatorubral-pallidoluysian atrophy.

150. The method of claim 147, wherein the disease is spinocerebellar ataxia.

151. The method of any of claims 147-150, wherein the pharmaceutical composition is administered by injection.

152. The method of any of claims 147-150, wherein the pharmaceutical composition is adminstered into the central nervous system.

153. The method of any of claims 147-150, wherein the pharmaceutical composition is adminstered into the cerebrospinal fluid.

154. The method of any of claims 147-150, wherein the pharmaceutical composition is adminstered by intracerebroventricular administration.

155. The method of any of claims 147-150, wherein the pharmaceutical composition is administered intrathecally.

156. The method of any of claims 147-150, wherein the pharmaceutical composition is administered into the brain.

157. The method of any of claims 147-156, wherein the administration comprises a bolus injection.

158. The method of any of claims 147-157, wherein the administration comprises an infusion.

159. The method of claim 158, wherein the administration comprises an infusion by infusion pump.

160. A method of modulating the splicing of a pre-mRNA, comprising contacting a cell with a compound of any of claims 1 to 134.

161. A method of modulating the splicing of a pre-mRNA containing an expanded CAG repeat,

comprising contacting a cell with a compound of any of claims 1 to 134.

162. A method of modulating the splicing of an ATXN-3 pre-mRNA, comprising contacting a cell with a compound of any of claims 1 to 134.

163. A method of modulating the splicing of a mutant ATXN-3 pre-mRNA, comprising contacting a cell with a compound of any of claims 1 to 134.

164. A method of modulating the splicing of a mutant ATXN-3 pre-mRNA containing an expanded CAG repeat, comprising contacting a cell with a compound of any of claims 1 to 134.

165. A method of increasing the exclusion of ex on 10 of ATXN-3, comprising contacting a cell with a compound of any of claims 1 to 134.

166. A method of modulating the splicing of a ATXN-3 pre-mRNA, comprising contacting a cell with an ss-siRNA compound targeted to a repeat region.

167. A method of modulating the splicing of a mutant ATXN-3 pre-mRNA containing an expanded CAG repeat, comprising contacting a cell with an ss-siRNA compound targeted to a repeat region.

168. Use of a compound according to any of claims 1-134 or the pharmaceutical composition of claim 146 for the preparation of a medicament for use in the treatment of Spinocerebellar ataxia type 3.

169. Use of a compound according to any of claims 1-134 or the pharmaceutical composition of claim 146 for modulating the splicing of ATXN-3 pre-mRNA.