THERAPEUTIC COMPOUNDS

• US 20160251653A1
• Filed: 09/24/2015
• Published: 09/01/2016
• Est. Priority Date: 02/12/2011
• Status: Abandoned Application

• Current Assignee: University of Iowa Research Foundation
• Original Assignee: University of Iowa Research Foundation
• Inventors: Davidson, Beverly L., Boudreau, Ryan L.
• Application Number:
  US14/864,356
• Publication Number:
  US 20160251653A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: C12N 15/11 DNA or RNA fragments; Modified forms thereof DNA or RNA not used in recombinant technology, C07H21/00; Non-coding nucleic acids having a biological activity
• 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 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/53 reducing unwanted side-effects
• CPC Class Codes: C12N 2330/51 Specially adapted vectors
• CPC Class Codes: C12N 2750/14143 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention is directed to RNA interference (RNAi) molecules targeted against a Huntington'"'"'s disease nucleic acid sequence, and methods of using these RNAi molecules to treat Huntington'"'"'s disease.

Claims

1-72. -72. (canceled)

73. A nucleic acid encoding an artificial primary miRNA transcript (pri-miRNA) comprising, in order of position, a 5′

-flanking region, wherein the 5′

-flanking region comprises a 5′

-bulge sequence positioned upstream from a 5′

-joining sequence;

a non-guide region, wherein the 5′

-joining sequence is contiguously linked to the non-guide region;

a loop region;

a guide region; and

a 3′

-flanking region, wherein the guide region comprises a sequence at least 80% identical to cgaccaugcgagccagca (miHDS.1 guide. SEQ ID NO;

7) and the non-guide region is at least 80% complementary to the guide region.

74. The nucleic acid of claim 73, wherein the guide region consists of 18-30 nucleotides.

75. The nucleic acid of claim 73, wherein the 5′

joining sequence consists of 5-8 nucleotides.

76. The nucleic acid of claim 73, wherein the 5′

-bulge sequence consists of 1-10 nucleotides.

77. The nucleic acid of claim 73, wherein the 5′

-flanking region further comprises a 5′

-spacer sequence positioned upstream from the 5′

-bulge sequence.

78. The nucleic acid of claim 77, wherein the 5′

-spacer sequence consists of 10-12 nucleotides.

79. The nucleic acid of claim 77, further comprising a 5′

-upstream sequence positioned upstream from the 5′

-spacer sequence.

80. The nucleic acid of claim 79, wherein the 5′

-upstream sequence consists of 30-2000 nucleotides.

81. The nucleic acid of claim 73, wherein the 3′

-flanking region comprises a 3′

-joining sequence contiguously linked to the guide region.

82. The nucleic acid of claim 81, wherein the 3′

-joining sequence consists of 5-8 nucleotides.

83. The nucleic acid of claim 81, wherein the 3′

-joining sequence is at least about 85% complementary to the 5′

-joining sequence.

84. The nucleic acid of claim 81, further comprising a 3′

-bulge sequence positioned downstream from the 3′

-joining sequence.

85. The nucleic acid of claim 84, wherein the 3′

-bulge sequence consists of 1-10 nucleotides.

86. The nucleic acid of claim 84, further comprising a 3′

-spacer sequence positioned downstream from the 3′

-bulge sequence.

87. The nucleic acid of claim 86, wherein the 3′

-spacer sequence consists of 10-12 nucleotides.

88. The nucleic acid of claim 86, further comprising a 3′

-downstream sequence positioned downstream from the 3′

-spacer sequence.

89. The nucleic acid of claim 88, wherein the 3′

-downstream sequence is about 30-2000 nucleotides in length.

90. The nucleic acid of claim 73, wherein the loop region is from 15-25 nucleotides in length.

91. An expression cassette comprising a promoter contiguously linked to the nucleic acid of claim 73.

92. A vector comprising the expression cassette of claim 91.

93. The vector of claim 90, wherein the vector is an adeno-associated virus (AAV) vector.

94. The vector of claim 93, wherein the AAV is AAV1, AAV2, AAV4, AAV5, or AAV2/1.

95. An isolated microRNA molecule comprising the nucleic acid of claim 73.

96. A method of inducing RNA interference comprising administering to a subject an effective amount of the nucleic acid of claim 73.

97. A method of treating a subject with Huntington'"'"'s Disease, comprising administering to the subject the nucleic acid of claim 73 so as to treat the Huntington'"'"'s Disease.