Rna agents for gst-pi gene modulation

Patent metadata

Field	Value
Publication number	US-2016208254-A1
Application number	US-201514979567-A
Country	US
Kind code	A1
Filing date	Dec 28, 2015
Priority date	Dec 26, 2014
Publication date	Jul 21, 2016
Grant date	—

Abstract

This invention provides compounds, compositions and methods for modulating the expression of human GST-π using RNA interference. The RNA interference molecules can be used in methods for preventing or treating diseases such as malignant tumor. A nucleic acid molecule can have a) a polynucleotide sense strand and a polynucleotide antisense strand; b) each strand of the molecule being from 15 to 30 nucleotides in length; c) a contiguous region of from 15 to 30 nucleotides of the antisense strand being complementary to a sequence of an mRNA encoding GST-π; and d) at least a portion of the sense strand can be complementary to at least a portion of the antisense strand, and the molecule has a duplex region of from 15 to 30 nucleotides in length.

First claim

What is claimed is:

1 . A nucleic acid molecule, wherein:
a) the molecule has a polynucleotide sense strand and a polynucleotide antisense strand; b) each strand of the molecule is from 15 to 30 nucleotides in length; c) a contiguous region of from 15 to 30 nucleotides of the antisense strand is complementary to a sequence of an mRNA encoding GST-π; d) at least a portion of the sense strand is complementary to at least a portion of the antisense strand, and the molecule has a duplex region of from 15 to 30 nucleotides in length.

2 . The nucleic acid molecule of claim 1 , wherein the antisense strand is SEQ ID NO:1341, and the sense strand is SEQ ID NO:1276, or chemically modified strands thereof.

3 . The nucleic acid molecule of claim 1 , wherein the antisense strand is SEQ ID NO:1305, and the sense strand is SEQ ID NO:1240, or chemically modified strands thereof.

4 . The nucleic acid molecule of claim 1 , wherein the contiguous region of from 15 to 30 nucleotides of the antisense strand that is complementary to a sequence of an mRNA encoding GST-π is located in the duplex region of the molecule.

5 . The nucleic acid molecule of claim 1 , wherein the contiguous region of from 15 to 30 nucleotides of the antisense strand that is complementary to a sequence of an mRNA encoding GST-π is selected from a sequence of human GSTP1, wherein human GSTP1 mRNA is SEQ ID NO:1.

6 . The nucleic acid molecule of claim 1 , wherein the sequence of an mRNA encoding GST-π is selected from the group consisting of 5′UTR positions 1 to 249 of SEQ ID NO:1, CDS positions 250 to 882 of SEQ ID NO:1, and 3′UTR positions 883 to 986 of SEQ ID NO:1.

7 . The nucleic acid molecule of claim 1 , wherein the antisense strand contains a sequence selected from any one of SEQ ID NOs:609-1215.

8 . The nucleic acid molecule of claim 1 , wherein the antisense strand contains a sequence selected from any one of SEQ ID NOs:1281-1345.

9 . The nucleic acid molecule of claim 1 , wherein the molecule is composed of an antisense and sense strand pair selected from the group consisting of SEQ ID NO:1240 and 1305, SEQ ID NO:1265 and 1330, SEQ ID NO:1267 and 1332, SEQ ID NO:1269 and 1334, and SEQ ID NO:1276 and 1341.

10 . The nucleic acid molecule of claim 1 , wherein each strand of the molecule is from 18 to 22 nucleotides in length.

11 . The nucleic acid molecule of claim 1 , wherein the duplex region is 19 nucleotides in length.

12 . The nucleic acid molecule of claim 1 , wherein the polynucleotide sense strand and the polynucleotide antisense strand are connected as a single strand, and form a duplex region connected at one end by a loop.

13 . The nucleic acid molecule of claim 1 , wherein the molecule has a blunt end.

14 . The nucleic acid molecule of claim 1 , wherein the molecule has one or more 3′ overhangs.

15 . The nucleic acid molecule of claim 1 , wherein the molecule is an RNAi molecule active for gene silencing.

16 . The nucleic acid molecule of claim 1 , wherein the molecule is a dsRNA, a siRNA, a micro-RNA, or a shRNA active for gene silencing.

17 . The nucleic acid molecule of claim 1 , wherein the molecule is active for inhibiting expression of GST-π.

18 . The nucleic acid molecule of claim 1 , wherein the molecule has an 1050 for knockdown of GST-π of less than 100 pM.

19 . A composition comprising one or more nucleic acid molecules of claim 1 and a pharmaceutically acceptable carrier.

20 . The composition of claim 19 , wherein the carrier is a lipid molecule or liposome.

21 . A method for treating a disease associated with GST-π expression, the method comprising administering to a subject in need a composition of claim 19 .

22 . The method of claim 21 , wherein the disease is malignant tumor.

23 . The method of claim 22 , wherein the malignant tumor is presented in a disease selected from the group consisting of cancers associated with GST-π expression, cancers caused by cells expressing mutated KRAS, sarcomas, fibrosarcoma, malignant fibrous histiocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, chondrosarcoma, osteosarcoma, carcinomas, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, duodenal cancer, colorectal cancer, colon cancer, liver cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, kidney cancer, urethral cancer, bladder cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, skin cancer, bone cancer, leukemia, malignant lymphoma, epithelial malignant tumors, and non-epithelial malignant tumors.

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Minomi Kenjirou
• Takahashi Hirokazu
• Terada Erika
• Harborth Jens
• Cina Cima
• Zhang Jun
• Ahmadian Mohammad
• Ying Wenbin

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C12N2310/344

  Position-specific modifications, e.g. on every purine, at the 3'-end · CPC title

• C07F9/6533

  Six-membered rings · CPC title

• C12Q1/02

  involving viable microorganisms · CPC title