Modulation of hsp47 expression

Patent metadata

Field	Value
Publication number	US-2016108399-A1
Application number	US-201514924284-A
Country	US
Kind code	A1
Filing date	Oct 27, 2015
Priority date	Dec 9, 2009
Publication date	Apr 21, 2016
Grant date	—

Abstract

Provided herein are compositions, methods and kits for modulating expression of target genes, particularly heat shock protein 47 (hsp47). The compositions, methods and kits may include nucleic acid molecules (for example, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA) or short hairpin RNA (shRNA)) that modulate a gene encoding hsp47, for example, the gene encoding human hsp47. The composition and methods disclosed herein may also be used in treating conditions and disorders associated with hsp47 such as liver fibrosis, pulmonary fibrosis, peritoneal fibrosis and kidney fibrosis.

First claim

1 . A method for treating an individual suffering from a disease associated with hsp47 comprising administering to said individual the double stranded nucleic acid molecule of claim 38 in an amount sufficient to reduce expression of hsp47.

2 . The double stranded nucleic acid molecule of claim 38 having a structure (A2) set forth below:

(A2)
5′ N 1 -(N)x-Z 3′ (antisense strand)

3′ Z′-N 2 -(N′)y-z″ 5′ (sense strand)

wherein each of N 2 , N and N′ is independently an unmodified or modified ribonucleotide, or an unconventional moiety;
wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the adjacent N or N′ by a covalent bond;
wherein each of x and y is independently an integer between 17 and 39;
wherein the sequence of (N′)y has complementarity to the sequence of (N)x and the sequence of (N)x has complementarity to a consecutive sequence in a mRNA encoding hsp47;
wherein N 1 is covalently bound to (N)x and is mismatched to the mRNA encoding hsp47; or is a complementary DNA moiety to the mRNA encoding hsp47;
wherein N 1 is a moiety selected from natural or modified uridine or deoxyribouridine, ribothymidine, deoxyribothymidine, adenosine or deoxyadenosine;
wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of N 2 —(N′)y;
wherein each of Z and Z′ is independently present or absent, but if present is independently 1-5 consecutive nucleotides, consecutive non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present; and
wherein the sense strand and the antisense strand comprise the oligonucleotides described as SERPINH1_3 (SEQ ID NOS: 61 and 128), SERPINH1_5 (SEQ ID NOS: 62 and 129), SERPINH1_6 (SEQ ID NOS: 63 and 130), SERPINH1_7 (SEQ ID NOS: 64 and 131), SERPINH1_8 (SEQ ID NOS: 65 and 132), SERPINH1_9 (SEQ ID NOS: 66 and 133), SERPINH1_10 (SEQ ID NOS: 67 and 134), SERPINH1_11 (SEQ ID NOS: 68 and 135), SERPINH1_13 (SEQ ID NOS: 69 and 136), SERPINH1_14 (SEQ ID NOS: 70 and 137), SERPINH1_15 (SEQ ID NOS: 71 and 138), SERPINH1_16 (SEQ ID NOS: 72 and 139), SERPINH1_17 (SEQ ID NOS: 73 and 140), SERPINH1_19 (SEQ ID NOS: 74 and 141), SERPINH1_20 (SEQ ID NOS: 75 and 142), SERPINH1_21 (SEQ ID NOS: 76 and 143), SERPINH1_22 (SEQ ID NOS: 77 and 144), SERPINH1_23 (SEQ ID NOS: 78 and 145), SERPINH1_24 (SEQ ID NOS: 79 and 146), SERPINH1_25 (SEQ ID NOS: 80 and 147), SERPINH1_26 (SEQ ID NOS: 81 and 148), SERPINH1_27 (SEQ ID NOS: 82 and 149), SERPINH1_28 (SEQ ID NOS: 83 and 150), SERPINH1_31 (SEQ ID NOS: 84 and 151), SERPINH1_32 (SEQ ID NOS: 85 and 152), SERPINH1_33 (SEQ ID NOS: 86 and 153), SERPINH1_34 (SEQ ID NOS: 87 and 154), SERPINH1_35 (SEQ ID NOS: 88 and 155), SERPINH1_36 (SEQ ID NOS: 89 and 156), SERPINH1_37 (SEQ ID NOS: 90 and 157), SERPINH1_38 (SEQ ID NOS: 91 and 158), SERPINH1_39 (SEQ ID NOS: 92 and 159), SERPINH1_41 (SEQ ID NOS: 93 and 160), SERPINH1_42 (SEQ ID NOS: 94 and 161), SERPINH1_43 (SEQ ID NOS: 95 and 162), SERPINH1_44 (SEQ ID NOS: 96 and 163), SERPINH1_48 (SEQ ID NOS: 99 and 166), SERPINH1_49 (SEQ ID NOS: 100 and 167), SERPINH1_52 (SEQ ID NOS: 102 and 169), SERPINH1_53 (SEQ ID NOS: 103 and 170), SERPINH1_59 (SEQ ID NOS: 104 and 171), SERPINH1_61 (SEQ ID NOS: 106 and 173), SERPINH1_62 (SEQ ID NOS: 107 and 174), SERPINH1_64 (SEQ ID NOS: 108 and 175), SERPINH1_65 (SEQ ID NOS: 109 and 176), SERPINH1_66 (SEQ ID NOS: 110 and 177), SERPINH1_68 (SEQ ID NOS: 111 and 178), SERPINH1_69 (SEQ ID NOS: 112 and 179), SERPINH1_70 (SEQ ID NOS: 113 and 180), SERPINH1_71 (SEQ ID NOS: 114 and 181), SERPINH1_74 (SEQ ID NOS: 115 and 182), SERPINH1_75 (SEQ ID NOS: 116 and 183), SERPINH1_77 (SEQ ID NOS: 117 and 184), SERPINH1_78 (SEQ ID NOS: 118 and 185), SERPINH1_80 (SEQ ID NOS: 119 and 186), SERPINH1_82 (SEQ ID NOS: 120 and 187), SERPINH1_83 (SEQ ID NOS: 121 and 188), SERPINH1_84 (SEQ ID NOS: 122 and 189), SERPINH1_86 (SEQ ID NOS: 123 and 190), SERPINH1_87 (SEQ ID NOS: 124 and 191), SERPINH1_89 (SEQ ID NOS: 125 and 192) or SERPINH1_90 (SEQ ID NOS: 126 and 193).

3 . A composition comprising the double stranded nucleic acid molecule of claim 38 ; and a pharmaceutically acceptable carrier.

4 . The method of claim 1 , wherein the disease associated with hsp47 is fibrosis.

5 . The double stranded nucleic acid molecule of claim 38 , having the structure

5′    UACUCGUCUCGCAUCUUGU-Z 3′
(antisense SEQ ID

      |||||||||||||||||||
NO: 130)

3′ Z′-AUGAGCAGAGCGUAGAACA-z″ 5′
(sense SEQ ID NO:

63)

or

5′    ACACCCAUGUGUCUCAGGA-Z 3′
(antisense SEQ ID

      |||||||||||||||||||
NO: 172)

3′ Z′-UGUGGGUACACAGAGUCCU-z″ 5′
(sense SEQ ID NO:

105)

or

5′    AAUAGCACCCAUGUGUCUC-Z 3′
(antisense SEQ ID

      |||||||||||||||||||
NO: 220)

3′ Z′-UUAUCGUGGGUACACAGAG-z″ 5′
(sense SEQ ID NO:

195)

or

5′    AACUCGUCUCGCAUCUUGU-Z 3′
(antisense SEQ ID

      |||||||||||||||||||
NO: 221)

3′ Z′-UUGAGCAGAGCGUAGAACA-z″ 5′
(sense SEQ ID NO:

196)

wherein each “|” represents base pairing between the ribonucleotides;
wherein each of A, C, G and U is independently an unmodified or modified ribonucleotide, or an unconventional moiety;
wherein each A, C, G and U is joined to an adjacent A, C, G or U by a covalent bond;
wherein each of Z and Z′ is independently present or absent, but if present is independently 1-5 consecutive nucleotides or non-nucleotide moieties or a combination thereof covalently attached at the 3′ terminus of the strand in which it is present; and
wherein z″ may be present or absent, but if present is a capping moiety covalently attached at t

Assignees

• Nitto Denko Corp

Inventors

• Jin Xiaomei
• Yu Lei
• Takahashi Hirokazu
• Tanaka Yasunobu
• Niitsu Yoshiro
• Feinstein Elena
• Avkin-Nachum Sharon
• Kalinski Hagar
• Mett Igor
• Erlich Shai
• Squiers Elizabeth C
• Chen Ning

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P41/00

  Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title