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Locked nucleic acid inhibitor of miR-145 and uses thereof

A technology for locking nucleic acids and nucleotides, which is applied in the field of locking nucleic acid inhibitors of MIR-145 and its application, and can solve problems such as loss of activity and attack

Inactive Publication Date: 2015-12-23
MIRAGEN THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, when oligonucleotides are introduced into intact cells, they are often attacked and degraded by nucleases, resulting in loss of activity

Method used

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  • Locked nucleic acid inhibitor of miR-145 and uses thereof
  • Locked nucleic acid inhibitor of miR-145 and uses thereof
  • Locked nucleic acid inhibitor of miR-145 and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: In vivo efficacy of AntimiR-145 compounds.

[0130] To optimize compounds targeting miR-145 in the lung, an in vivo screen was performed using derepression of the direct mRNA target of miR-145 in the lung as a readout for in vivo functionality.

[0131] A total of 9 different antimiR designs were tested in rats, as depicted in Table 1:

[0132]

[0133]

[0134] Table 2: Description of symbols

[0135] Deoxy A

a

Deoxy-G

g

Deoxy C

c

Deoxy T

t

lna A

A

wxya

G

lna C

C

lna T

T

[0136] The nine antimiR compounds in Table 1 were assayed for target derepression in Sprague-Dawley rats. 49 to 52 day old Sprague-Dawley rats were injected subcutaneously with antimiR compounds from Table 1 at a dose of 25 mg / kg. Saline and oligonucleotides with similar LNA and DNA percentages (9 / 7) were used as controls. Oligonucleotide control Molecular No. M-10591 was designed t...

Embodiment 2

[0139] Example 2: MiR-145 specificity of AntimiR-145 compounds.

[0140] 49 to 52 day old Sprague-Dawley rats were injected subcutaneously with saline or M-11318 at a dose of 25 mg / kg. Total RNA from the lungs of M-11318-treated and saline-treated rats was subjected to genome-wide profiling using microarray profiling. When comparing total RNA from the lungs of M-11318-treated rats with that from saline-treated rats, genes containing miR-145 seeds were enriched in the upregulated gene signature (for differential expression, p - value image 3 ). This result indicates that M-11318 triggers derepression of gene targets specific for miR-145.

Embodiment 3

[0141] Example 3: Dose-dependent target derepression by AntimiR-145 compound M-11318.

[0142]49 to 52 days old with saline at a dose of 25 mg / kg, M-10591 at a dose of 25 mg / kg, M-10934 at a dose of 25 mg / kg, or M-11318 at a dose of 5 mg / kg, 10 mg / kg, or 25 mg / kg Sprague-Dawley rats. Lung tissue was collected 72 hours after injection. The mRNA of Klf5 in total lung RNA was measured by real-time PCR. Figure 4 Results are shown in fold change values ​​relative to saline-treated animals. Real-time PCR results indicated that KLF5 target derepression was dose-responsive to M-11318 treatment.

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Abstract

The present invention provides oligonucleotides with chemical motifs that are miR-145 inhibitors. The oligonucleotides can be used for the treatment and prevention of a condition by inhibiting the expression or activity of miR-145 in cells of a subject in need thereof. Methods provided include treating or preventing pulmonary arterial hypertension, neointima formation, restenosis or hypertension in a subject in need thereof by administering to the subject an inhibitor of miR-145 expression or activity. Pharmaceutical compositions and kits comprising miR-145 inhibitors are also disclosed.

Description

[0001] cross reference [0002] This application claims the benefit of US Provisional Application No. 61 / 800,755, filed March 15, 2013, which is hereby incorporated by reference in its entirety. [0003] Description of electronically submitted text files [0004] The contents of the text file electronically filed with this article are incorporated herein by reference in their entirety: Computer-readable copy of the sequence listing (file name: MIRG_41_01WO_SeqList_ST25.txt, date of record: March 13, 2014, file size 5 kilobytes) . field of invention [0005] In general, the present invention relates to oligonucleotides having chemical motifs that are inhibitors of miR-145. Oligonucleotides of the invention may have advantages in potency, delivery efficiency, target specificity, stability, and / or toxicity when administered to a subject. Oligonucleotides can be used to treat and prevent conditions by inhibiting the expression or activity of miR-145 in cells of a subject in nee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/712
CPCA61K31/713A61P9/12A61P11/00A61P43/00C07H21/00C12N15/113C12N2310/113C12N2310/3231C12N2310/315C12N2310/321C12N2310/322
Inventor A.G.塞托E.V.罗伊K.H.鲁宾逊C.M.多尔比T.G.赫林格R.蒙哥马利
Owner MIRAGEN THERAPEUTICS
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