Methods and sequences to preferentially suppress expression of mutated huntingtin

• US 20070161590A1
• Filed: 06/28/2006
• Published: 07/12/2007
• Est. Priority Date: 06/28/2005
• Status: Abandoned Application

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Jaspers, Leonie, Van Bilsen, Paul
• Application Number:
  US11/478,110
• Publication Number:
  US 20070161590A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/53 partially self-complementary or closed
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

Disclosed herein are methods and sequences to preferentially suppress the expression of the mutated huntingtin (“htt”) protein over expression of the normal htt protein. Also disclosed are methods comprising screening an individual for the heterozygous presence of one or more single nucleotide polymorphisms within the individual'"'"'s Huntington'"'"'s genes; administering nucleic acid molecules comprising nucleotide sequences that preferentially suppress the expression of amino acid sequences encoding for mutated huntingtin (“htt”) over suppressing the expression of amino acid sequences encoding for normal htt by targeting an area of a Huntington'"'"'s disease gene that is heterozygous for the presence of one or more single nucleotide polymorphisms.

Claims

1. A method comprising:

administering to an individual nucleic acid molecules comprising nucleotide sequences that preferentially suppress the expression of amino acid sequences encoding for mutated huntingtin (“

htt”

) over suppressing the expression of amino acid sequences encoding for normal htt by targeting an area of a Huntington'"'"'s disease gene that is heterozygous for the presence of one or more single nucleotide polymorphisms wherein said individual has been screened for the heterozygous presence of one or more single nucleotide polymorphisms within said individual'"'"'s Huntington'"'"'s genes.

2. A method according to claim 1, wherein said nucleic acid molecules comprise nucleotide sequences selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

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SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

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SEQ ID NO;

17;

SEQ ID NO;

18;

SEQ ID NO;

19;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

69;

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70;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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90;

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91;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134;

SEQ ID NO;

135; and

combinations thereof.

3. A method according to claim 1, wherein said nucleic acid molecules comprise nucleotide sequences selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

18;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

31;

SEQ ID NO;

32;

SEQ ID NO;

33;

SEQ ID NO;

34;

SEQ ID NO;

35;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

38;

SEQ ID NO;

39;

SEQ ID NO;

40;

SEQ ID NO;

41;

SEQ ID NO;

42;

SEQ ID NO;

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SEQ ID NO;

44;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

48;

SEQ ID NO;

49;

SEQ ID NO;

50;

SEQ ID NO;

51;

SEQ ID NO;

52;

SEQ ID NO;

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SEQ ID NO;

54;

SEQ ID NO;

55;

SEQ ID NO;

56;

SEQ ID NO;

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SEQ ID NO;

58;

SEQ ID NO;

59;

SEQ ID NO;

60;

SEQ ID NO;

61;

SEQ ID NO;

62;

SEQ ID NO;

63;

SEQ ID NO;

64;

SEQ ID NO;

65;

SEQ ID NO;

66;

SEQ ID NO;

67;

SEQ ID NO;

68;

SEQ ID NO;

69;

SEQ ID NO;

70;

SEQ ID NO;

71;

SEQ ID NO;

72;

SEQ ID NO;

73;

SEQ ID NO;

74;

SEQ ID NO;

75;

SEQ ID NO;

76;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

80;

SEQ ID NO;

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SEQ ID NO;

82;

SEQ ID NO;

83;

SEQ ID NO;

84;

SEQ ID NO;

85;

SEQ ID NO;

86;

SEQ ID NO;

87;

SEQ ID NO;

88;

SEQ ID NO;

89;

SEQ ID NO;

90;

SEQ ID NO;

91;

SEQ ID NO;

92;

SEQ ID NO;

93;

SEQ ID NO;

94;

SEQ ID NO;

95;

SEQ ID NO;

96;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

99;

SEQ ID NO;

100;

SEQ ID NO;

101;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

106;

SEQ ID NO;

107;

SEQ ID NO;

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SEQ ID NO;

109;

SEQ ID NO;

110;

SEQ ID NO;

114;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

120;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

123;

SEQ ID NO;

124;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

127;

SEQ ID NO;

128;

SEQ ID NO;

129;

SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134;

SEQ ID NO;

135; and

combinations thereof in shNA format.

4. A method according to claim 1, wherein said nucleic acid molecules are administered to an area selected from the group consisting of the intrathecal space of the spinal cord;

the striatum;

intracranially; and

combinations thereof.

5. A method according to claim 2, wherein said nucleic acid sequences are administered through an administration system selected from the group consisting of a depot, an infusion pump, an osmotic pump, an interbody pump, a catheter, and combinations thereof.

6. A method according to claim 2, wherein said nucleic acid sequences are administered through an implanted pump that controls the delivery of said nucleic acid sequences to an area selected from the group consisting of the intrathecal space of the spinal cord;

the striatum;

intracranially; and

combinations thereof wherein said nucleic acid sequences are delivered in a pharmaceutically effective amount to improve at least one symptom of Huntington'"'"'s disease.

7. A nucleic acid molecule comprising a nucleotide sequence that preferentially suppresses the expression of amino acid sequences encoding for mutated huntingtin (“

htt”

) over suppressing the expression of amino acid sequences encoding for normal htt wherein said nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO;

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

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SEQ ID NO;

15;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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60;

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61;

SEQ ID NO;

62;

SEQ ID NO;

63;

SEQ ID NO;

64;

SEQ ID NO;

65;

SEQ ID NO;

66;

SEQ ID NO;

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SEQ ID NO;

68;

SEQ ID NO;

69;

SEQ ID NO;

70;

SEQ ID NO;

71;

SEQ ID NO;

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73;

SEQ ID NO;

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SEQ ID NO;

90;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134; and

SEQ ID NO;

135.

8. A nucleic acid molecule according to claim 7, wherein said nucleotide sequence is a sequence selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

76;

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SEQ ID NO;

78;

SEQ ID NO;

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SEQ ID NO;

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86;

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SEQ ID NO;

90;

SEQ ID NO;

91;

SEQ ID NO;

92;

SEQ ID NO;

93;

SEQ ID NO;

94;

SEQ ID NO;

95;

SEQ ID NO;

96;

SEQ ID NO;

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SEQ ID NO;

98;

SEQ ID NO;

99;

SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

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SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134; and

SEQ ID NO;

135;

in shNA format.

9. An expression cassette comprising a nucleotide sequence wherein said sequence is a human sequence selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

16;

SEQ ID NO;

17;

SEQ ID NO;

18;

SEQ ID NO;

19;

SEQ ID NO;

20;

SEQ ID NO;

21;

SEQ ID NO;

22;

SEQ ID NO;

23;

SEQ ID NO;

24;

SEQ ID NO;

25;

SEQ ID NO;

26;

SEQ ID NO;

27;

SEQ ID NO;

28;

SEQ ID NO;

29;

SEQ ID NO;

30;

SEQ ID NO;

31;

SEQ ID NO;

32;

SEQ ID NO;

33;

SEQ ID NO;

34;

SEQ ID NO;

35;

SEQ ID NO;

36;

SEQ ID NO;

37;

SEQ ID NO;

38;

SEQ ID NO;

39;

SEQ ID NO;

40;

SEQ ID NO;

41;

SEQ ID NO;

42;

SEQ ID NO;

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SEQ ID NO;

44;

SEQ ID NO;

45;

SEQ ID NO;

46;

SEQ ID NO;

47;

SEQ ID NO;

48;

SEQ ID NO;

49;

SEQ ID NO;

50;

SEQ ID NO;

51;

SEQ ID NO;

52;

SEQ ID NO;

53;

SEQ ID NO;

54;

SEQ ID NO;

55;

SEQ ID NO;

56;

SEQ ID NO;

57;

SEQ ID NO;

58;

SEQ ID NO;

59;

SEQ ID NO;

60;

SEQ ID NO;

61;

SEQ ID NO;

62;

SEQ ID NO;

63;

SEQ ID NO;

64;

SEQ ID NO;

65;

SEQ ID NO;

66;

SEQ ID NO;

67;

SEQ ID NO;

68;

SEQ ID NO;

69;

SEQ ID NO;

70;

SEQ ID NO;

71;

SEQ ID NO;

72;

SEQ ID NO;

73;

SEQ ID NO;

74;

SEQ ID NO;

75;

SEQ ID NO;

76;

SEQ ID NO;

77;

SEQ ID NO;

78;

SEQ ID NO;

79;

SEQ ID NO;

80;

SEQ ID NO;

81;

SEQ ID NO;

82;

SEQ ID NO;

83;

SEQ ID NO;

84;

SEQ ID NO;

85;

SEQ ID NO;

86;

SEQ ID NO;

87;

SEQ ID NO;

88;

SEQ ID NO;

89;

SEQ ID NO;

90;

SEQ ID NO;

91;

SEQ ID NO;

92;

SEQ ID NO;

93;

SEQ ID NO;

94;

SEQ ID NO;

95;

SEQ ID NO;

96;

SEQ ID NO;

97;

SEQ ID NO;

98;

SEQ ID NO;

99;

SEQ ID NO;

100;

SEQ ID NO;

101;

SEQ ID NO;

102;

SEQ ID NO;

103;

SEQ ID NO;

104;

SEQ ID NO;

105;

SEQ ID NO;

106;

SEQ ID NO;

107;

SEQ ID NO;

108;

SEQ ID NO;

109;

SEQ ID NO;

110;

SEQ ID NO;

114;

SEQ ID NO;

115;

SEQ ID NO;

116;

SEQ ID NO;

117;

SEQ ID NO;

118;

SEQ ID NO;

119;

SEQ ID NO;

120;

SEQ ID NO;

121;

SEQ ID NO;

122;

SEQ ID NO;

123;

SEQ ID NO;

124;

SEQ ID NO;

125;

SEQ ID NO;

126;

SEQ ID NO;

127;

SEQ ID NO;

128;

SEQ ID NO;

129;

SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134; and

SEQ ID NO;

135.

10. An expression cassette according to claim 9, further comprising a regulatable or a constitutive promoter operably linked to said nucleic acid sequence.

11. A cell comprising the expression cassette of claim 9.

12. A vector comprising the expression cassette of claim 9.

13. A vector according to claim 12, wherein said vector is a viral vector selected from the group consisting of an adenoviral virus vector, a retroviral virus vector, a parvoviral virus vector, a picornaviral virus vector, and a herpes virus vector.

14. A vector according to claim 11, wherein said vector comprises a regulatable or a constitutive promoter operably linked to said nucleic acid sequence.

15. A kit for screening individuals for the heterozygous presence of one or more single nucleotide polymorphisms within said individual'"'"'s Huntington'"'"'s genes.

16. A kit according to claim 15, wherein said kit comprises at least one molecular beacon that detects a single nucleotide polymorphism found in a sequence selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

16;

SEQ ID NO;

17;

SEQ ID NO;

18;

SEQ ID NO;

19;

SEQ ID NO;

20;

SEQ ID NO;

21; and

SEQ ID NO;

22 wherein said molecular beacon comprises at least a portion of the reverse complement of said sequence containing said detected single nucleotide polymorphism.

17. A kit according to claim 15, wherein said kit further comprises nucleic acid molecules that preferentially suppress the expression of amino acid sequences encoding for mutated huntingtin (“

htt”

) over suppressing the expression of amino acid sequences encoding for normal hit by targeting an area of a Huntington'"'"'s disease gene that is heterozygous for the presence of one or more single nucleotide polymorphisms.

18. A kit according to claim 17, wherein said nucleotide sequences are selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

16;

SEQ ID NO;

17;

SEQ ID NO;

18;

SEQ ID NO;

19;

SEQ ID NO;

20;

SEQ ID NO;

21;

SEQ ID NO;

22;

SEQ ID NO;

23;

SEQ ID NO;

24;

SEQ ID NO;

25;

SEQ ID NO;

26;

SEQ ID NO;

27;

SEQ ID NO;

28;

SEQ ID NO;

29;

SEQ ID NO;

30;

SEQ ID NO;

31;

SEQ ID NO;

32;

SEQ ID NO;

33;

SEQ ID NO;

34;

SEQ ID NO;

35;

SEQ ID NO;

36;

SEQ ID NO;

37;

SEQ ID NO;

38;

SEQ ID NO;

39;

SEQ ID NO;

40;

SEQ ID NO;

41;

SEQ ID NO;

42;

SEQ ID NO;

43;

SEQ ID NO;

44;

SEQ ID NO;

45;

SEQ ID NO;

46;

SEQ ID NO;

47;

SEQ ID NO;

48;

SEQ ID NO;

49;

SEQ ID NO;

50;

SEQ ID NO;

51;

SEQ ID NO;

52;

SEQ ID NO;

53;

SEQ ID NO;

54;

SEQ ID NO;

55;

SEQ ID NO;

56;

SEQ ID NO;

57;

SEQ ID NO;

58;

SEQ ID NO;

59;

SEQ ID NO;

60;

SEQ ID NO;

61;

SEQ ID NO;

62;

SEQ ID NO;

63;

SEQ ID NO;

64;

SEQ ID NO;

65;

SEQ ID NO;

66;

SEQ ID NO;

67;

SEQ ID NO;

68;

SEQ ID NO;

69;

SEQ ID NO;

70;

SEQ ID NO;

71;

SEQ ID NO;

72;

SEQ ID NO;

73;

SEQ ID NO;

74;

SEQ ID NO;

75;

SEQ ID NO;

76;

SEQ ID NO;

77;

SEQ ID NO;

78;

SEQ ID NO;

79;

SEQ ID NO;

80;

SEQ ID NO;

81;

SEQ ID NO;

82;

SEQ ID NO;

83;

SEQ ID NO;

84;

SEQ ID NO;

85;

SEQ ID NO;

86;

SEQ ID NO;

87;

SEQ ID NO;

88;

SEQ ID NO;

89;

SEQ ID NO;

90;

SEQ ID NO;

91;

SEQ ID NO;

92;

SEQ ID NO;

93;

SEQ ID NO;

94;

SEQ ID NO;

95;

SEQ ID NO;

96;

SEQ ID NO;

97;

SEQ ID NO;

98;

SEQ ID NO;

99;

SEQ ID NO;

100;

SEQ ID NO;

101;

SEQ ID NO;

102;

SEQ ID NO;

103;

SEQ ID NO;

104;

SEQ ID NO;

105;

SEQ ID NO;

106;

SEQ ID NO;

107;

SEQ ID NO;

108;

SEQ ID NO;

109;

SEQ ID NO;

110;

SEQ ID NO;

114;

SEQ ID NO;

115;

SEQ ID NO;

116;

SEQ ID NO;

117;

SEQ ID NO;

118;

SEQ ID NO;

119;

SEQ ID NO;

120;

SEQ ID NO;

121;

SEQ ID NO;

122;

SEQ ID NO;

123;

SEQ ID NO;

124;

SEQ ID NO;

125;

SEQ ID NO;

126;

SEQ ID NO;

127;

SEQ ID NO;

128;

SEQ ID NO;

129;

SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134;

SEQ ID NO;

135; and

combinations thereof.

19. A kit according to claim 17, wherein said nucleotide sequences are selected from the group consisting of SEQ ID NO:

1;

SEQ ID NO;

2;

SEQ ID NO;

3;

SEQ ID NO;

4;

SEQ ID NO;

5;

SEQ ID NO;

6;

SEQ ID NO;

7;

SEQ ID NO;

8;

SEQ ID NO;

9;

SEQ ID NO;

10;

SEQ ID NO;

11;

SEQ ID NO;

12;

SEQ ID NO;

13;

SEQ ID NO;

14;

SEQ ID NO;

15;

SEQ ID NO;

16;

SEQ ID NO;

17;

SEQ ID NO;

18;

SEQ ID NO;

19;

SEQ ID NO;

20;

SEQ ID NO;

21;

SEQ ID NO;

22;

SEQ ID NO;

23;

SEQ ID NO;

24;

SEQ ID NO;

25;

SEQ ID NO;

26;

SEQ ID NO;

27;

SEQ ID NO;

28;

SEQ ID NO;

29;

SEQ ID NO;

30;

SEQ ID NO;

31;

SEQ ID NO;

32;

SEQ ID NO;

33;

SEQ ID NO;

34;

SEQ ID NO;

35;

SEQ ID NO;

36;

SEQ ID NO;

37;

SEQ ID NO;

38;

SEQ ID NO;

39;

SEQ ID NO;

40;

SEQ ID NO;

41;

SEQ ID NO;

42;

SEQ ID NO;

43;

SEQ ID NO;

44;

SEQ ID NO;

45;

SEQ ID NO;

46;

SEQ ID NO;

47;

SEQ ID NO;

48;

SEQ ID NO;

49;

SEQ ID NO;

50;

SEQ ID NO;

51;

SEQ ID NO;

52;

SEQ ID NO;

53;

SEQ ID NO;

54;

SEQ ID NO;

55;

SEQ ID NO;

56;

SEQ ID NO;

57;

SEQ ID NO;

58;

SEQ ID NO;

59;

SEQ ID NO;

60;

SEQ ID NO;

61;

SEQ ID NO;

62;

SEQ ID NO;

63;

SEQ ID NO;

64;

SEQ ID NO;

65;

SEQ ID NO;

66;

SEQ ID NO;

67;

SEQ ID NO;

68;

SEQ ID NO;

69;

SEQ ID NO;

70;

SEQ ID NO;

71;

SEQ ID NO;

72;

SEQ ID NO;

73;

SEQ ID NO;

74;

SEQ ID NO;

75;

SEQ ID NO;

76;

SEQ ID NO;

77;

SEQ ID NO;

78;

SEQ ID NO;

79;

SEQ ID NO;

80;

SEQ ID NO;

81;

SEQ ID NO;

82;

SEQ ID NO;

83;

SEQ ID NO;

84;

SEQ ID NO;

85;

SEQ ID NO;

86;

SEQ ID NO;

87;

SEQ ID NO;

88;

SEQ ID NO;

89;

SEQ ID NO;

90;

SEQ ID NO;

91;

SEQ ID NO;

92;

SEQ ID NO;

93;

SEQ ID NO;

94;

SEQ ID NO;

95;

SEQ ID NO;

96;

SEQ ID NO;

97;

SEQ ID NO;

98;

SEQ ID NO;

99;

SEQ ID NO;

100;

SEQ ID NO;

101;

SEQ ID NO;

102;

SEQ ID NO;

103;

SEQ ID NO;

104;

SEQ ID NO;

105;

SEQ ID NO;

106;

SEQ ID NO;

107;

SEQ ID NO;

108;

SEQ ID NO;

109;

SEQ ID NO;

110;

SEQ ID NO;

114;

SEQ ID NO;

115;

SEQ ID NO;

116;

SEQ ID NO;

117;

SEQ ID NO;

118;

SEQ ID NO;

119;

SEQ ID NO;

120;

SEQ ID NO;

121;

SEQ ID NO;

122;

SEQ ID NO;

123;

SEQ ID NO;

124;

SEQ ID NO;

125;

SEQ ID NO;

126;

SEQ ID NO;

127;

SEQ ID NO;

128;

SEQ ID NO;

129;

SEQ ID NO;

130;

SEQ ID NO;

131;

SEQ ID NO;

132;

SEQ ID NO;

133;

SEQ ID NO;

134;

SEQ ID NO;

135; and

combinations thereof in shNA format.

20. A kit according to claim 15, wherein said kit further comprises a vector comprising an expression cassette.

21. A kit according to claim 20, wherein said vector is a viral vector selected from the group consisting of an adenoviral virus vector, a retroviral virus vector, a parvoviral virus vector, a picornaviral virus vector, and a herpes virus vector.