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Microrna compounds and methods for modulating mir-21 activity




Title: Microrna compounds and methods for modulating mir-21 activity.
Abstract: Described herein are compositions and methods for the inhibition of miR-21 activity. The compositions have certain nucleoside modification patterns that yield potent inhibitors of miR-21 activity. The compositions may be used to inhibit miR-21, and also to treat diseases associated with abnormal expression of miR-21, such as fibrosis and cancer. ...


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USPTO Applicaton #: #20120270928
Inventors: Balkrishen Bhat


The Patent Description & Claims data below is from USPTO Patent Application 20120270928, Microrna compounds and methods for modulating mir-21 activity.

This application claims the benefit of priority to U.S. Provisional Application Nos. 61/478,767, filed Apr. 25, 2011, and 61/565,779, filed Dec. 1, 2011, which are incorporated herein by reference in their entireties for any purpose.

FIELD OF INVENTION

Provided herein are methods and compositions for the modulation of miR-21 activity.

DESCRIPTION OF RELATED ART

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MicroRNAs (microRNAs), also known as “mature microRNA” are small (approximately 18-24 nucleotides in length), non-coding RNA molecules encoded in the genomes of plants and animals. In certain instances, highly conserved, endogenously expressed microRNAs regulate the expression of genes by binding to the 3′-untranslated regions (3′-UTR) of specific mRNAs. More than 1000 different microRNAs have been identified in plants and animals. Certain mature microRNAs appear to originate from long endogenous primary microRNA transcripts (also known as pri-microRNAs, pri-mirs, pri-miRs or pri-pre-microRNAs) that are often hundreds of nucleotides in length (Lee, et al., EMBO J., 2002, 21(17), 4663-4670).

Functional analyses of microRNAs have revealed that these small non-coding RNAs contribute to different physiological processes in animals, including developmental timing, organogenesis, differentiation, patterning, embryogenesis, growth control and programmed cell death. Examples of particular processes in which microRNAs participate include stem cell differentiation, neurogenesis, angiogenesis, hematopoiesis, and exocytosis (reviewed by Alvarez-Garcia and Miska, Development, 2005, 132, 4653-4662).

SUMMARY

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OF INVENTION

Provided herein are compounds comprising a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 and wherein the modified oligonucleotide has a nucleoside pattern described herein.

Provided herein are methods for inhibiting the activity of miR-21 comprising contacting a cell with a compound described herein. In certain embodiments, the cell is in vivo. In certain embodiments, the cell is in vitro.

Provided herein are methods for treating a disease associated with miR-21 comprising administering to a subject having a disease associated with miR-21 a compound described herein. In certain embodiments, the animal is a human.

The compounds described herein are provided for use in therapy.

Provided herein are compounds comprising a modified oligonucleotide consisting of 8 to 22 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern I in the 5′ to 3′ orientation:


(R)X-NB-NQ-NQ-NB-(NQ-NQ-NQ-NB)3-NQ-NZ

wherein each R is, independently, a non-bicyclic nucleoside; X is from 1 to 4; each NB is, independently, a bicyclic nucleoside; each NQ is, independently, a non-bicyclic nucleoside; and each NZ is, independently, a modified nucleoside.

Provided herein are compounds comprising a modified oligonucleotide consisting of 8 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern II in the 5′ to 3′ orientation:


NM-NB-NQ-NQ-NB-(NQ-NQ-NQ-NB)3-NQ-NZ

wherein NM is, independently, a modified nucleoside that is not a bicyclic nucleoside; each NB is, independently, a bicyclic nucleoside; each NQ is, independently, a non-bicyclic nucleoside; and NZ is, independently, a modified nucleoside.

Provided herein are compounds comprising a modified oligonucleotide consisting of 8 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern III in the 5′ to 3′ orientation:


(R)X-NB-NQ-NQ-NB-(NQ-NQ-NQ-NB)3-NY-NZ

wherein each R is a non-bicyclic nucleoside; X is from 1 to 4; each NB is a bicyclic nucleoside; each NQ is a non-bicyclic nucleoside; NY is a modified nucleoside or an unmodified nucleoside; and each NZ is a modified nucleoside.

Provided herein are compounds comprising a modified oligonucleotide consisting of 8 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern IV in the 5′ to 3′ orientation:


NM-NB-NQ-NQ-NB-(NQ-NQ-NQ-NB)3-NY-NZ

wherein NM is a modified nucleoside that is not a bicyclic nucleoside; each NB is a bicyclic nucleoside; each NQ is a non-bicyclic nucleoside; NY is a modified nucleoside or an unmodified nucleoside; and NZ is a modified nucleoside.

Provided herein are compounds comprising a modified oligonucleotide consisting of 8 to 19 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern V in the 5′ to 3′ orientation:




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stats Patent Info
Application #
US 20120270928 A1
Publish Date
10/25/2012
Document #
File Date
12/31/1969
USPTO Class
Other USPTO Classes
International Class
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20121025|20120270928|microrna compounds and methods for modulating mir-21 activity|Described herein are compositions and methods for the inhibition of miR-21 activity. The compositions have certain nucleoside modification patterns that yield potent inhibitors of miR-21 activity. The compositions may be used to inhibit miR-21, and also to treat diseases associated with abnormal expression of miR-21, such as fibrosis and cancer. |Regulus-Therapeutics-Inc
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