Blood-borne miRNA as surrogate markers of drug efficacy for cardiac conditions

A technology for efficacy and heart disease, applied in the direction of drug combination, cardiovascular system diseases, active ingredients of heterocyclic compounds, etc., can solve problems such as hindering treatment, lack of molecular level diagnostic technology, and difficulty in determining the cause of heart failure

Inactive Publication Date: 2013-10-23
MIRAGEN THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the etiology of heart failure can be difficult to determine, a factor hindering the development of more specific treatments
Moreover, there is a general lack of diagnostic techniques at the molecular level

Method used

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  • Blood-borne miRNA as surrogate markers of drug efficacy for cardiac conditions
  • Blood-borne miRNA as surrogate markers of drug efficacy for cardiac conditions
  • Blood-borne miRNA as surrogate markers of drug efficacy for cardiac conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Example 1: Blood-borne miRNAs as Surrogate Markers of Drugs for Cardiac Disorders

[0156] The importance of miRNAs for cardiac function and dysfunction suggests an opportunity to therapeutically exploit the biology of miRNAs in the setting of cardiac disease. Single-stranded RNA oligonucleotides have been shown to be effective for inactivating miRNAs in vivo by complementary base pairing (Elmen, J. et al. (2008) Nature 452, 896-899; Elmen, J. et al. (2008) Nucleic Acids Res 36 , 1153-1162; Krutzfeldt, J. et al. (2007) Nucleic Acids Res35, 2885-2892; Krutzfeldt, J. et al. (2005) Nature 438, 685-689; Lanford, R.E. et al. (2010) Science 327, 198-201) , and represent a potentially effective means of inactivating pathological miRNAs.

[0157] This example describes the therapeutic efficacy of antisense oligonucleotides targeting miR-208a in a model of heart failure. Specifically, we show that systemic delivery of locked nucleotide (LNA)-modified antisense oligonucleotides...

Embodiment 2

[0171] Example 2: Plasma miRNAs are biomarkers of disease progression in heart failure and therapeutic efficacy of anti-miR-208 oligonucleotides.

[0172] To assess plasma biomarkers over time, a surgically implanted catheter was used to draw blood non-invasively every two weeks in the Dahl salt-sensitive rat model of congestive heart failure described in Example 1 . Changes in plasma miRNA biomarkers with disease progression were assessed following treatment with an LNA-modified antisense oligonucleotide (M-10101; SEQ ID NO: 12) targeting miR-208a. The following experimental groups were tested:

[0173] Group

Strain

diet

deal with

group 1

Dahl SS

regular feed

subcutaneous saline

group 2

Dahl SS

4% NaCl diet

subcutaneous saline

group 3

Dahl SS

4% NaCl diet

Subcutaneous M-10101 anti-miR (25mg / kg)

group 4

Dahl SS

4% NaCl diet

Subcutaneous M-10591 control (25mg / kg)

[0174]...

Embodiment 3

[0196] Example 3: Anti-miR Treatment and Captopril Treatment Affect Circulating miRs

[0197] The effect of different therapeutic approaches on plasma miRNA levels was assessed using the Dahl salt-sensitive rat model of congestive heart failure (see Example 1). Specifically, anti-miR-208a oligonucleotides containing LNA (M-10101), captopril (an angiotensin-converting enzyme (ACE) inhibitor) or a combination of both (M-10101+ Captopril) treated rats.

[0198] The following experimental groups were evaluated:

[0199] Group

Strain

N

diet

deal with

group 1

Dahl SS

6

regular food

Saline sc / water po

group 2

Dahl SS

10

6% NaCl diet

Saline sc / water po

group 3

Dahl SS

9

6% NaCl diet

M-10101(25mg / kg) sc / water po

group 4

Dahl SS

9

6% NaCl diet

Saline sc / captopril (1.5mg / kg) po

Group 5

Dahl SS

9

6% NaCl diet

Saline sc / captopril (15mg / kg) po

...

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Abstract

The present invention provides methods for evaluating or monitoring the efficacy of a therapeutic intervention for treating a cardiac disorder. Such methods comprise measuring or detecting the level of at least one miRNA in a biological sample from a patient receiving the therapeutic intervention and comparing the level to the level of said at least one miRNA in a control sample, wherein the measured level of said at least one miRNA is indicative of the therapeutic efficacy of the therapeutic intervention. Methods of predicting or assessing the severity or progression of heart failure in a patient by measuring one or more miRNAs in a biological sample from the patient are also disclosed.

Description

[0001] priority [0002] This application claims U.S. Provisional Application No. 61 / 538,585, filed September 23, 2011, U.S. Provisional Application No. 61 / 495,220, filed June 9, 2011, and U.S. Provisional Application No. 61 / 423,456, which is hereby incorporated in its entirety by reference to each of them. field of invention [0003] The present invention relates to the detection of microRNA levels for assessing or detecting the efficacy of a therapeutic intervention on a cardiac condition, or for assessing the severity of disease progression of heart failure in a patient. The invention further relates to treating cardiac disorders in patients. Background of the invention [0004] Current treatments for heart disease, including heart failure, include pharmacological methods, ventricular assist devices (ventricular assist device, VAD) and other devices, cardiac resynchronization therapy (cardiac resynchronization therapy, CRT), and heart transplantation. Pharmacological a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q2600/178G01N33/5308A61K31/7088C12Q1/68C12Q1/6883C12Q2600/118A61K31/40A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12
Inventor E.V.罗耶B.迪金森A.塞托
Owner MIRAGEN THERAPEUTICS
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