IP Library › Granted Patent US 9,611,511

Granted Patent B2

US 9,611,511 · App. 13/642,321 · Granted Apr 4, 2017

Complex miRNA sets as novel biomarkers for an acute coronary syndrome

Inventors: Andreas Keller (Püttlingen, DE); Peer F. Stähler (Mannheim, DE); Markus Beier (Weinheim, DE); Benjamin Meder (Dossenheim, DE); Hugo A. Katus (Heidelberg, DE); Wolfgang Rottbauer (Ulm, DE)

Assignee: COMPREHENSIVE BIOMARKER CENTER GMBH

C12Q1/6876 C12Q1/6883 C12Q2600/158 C12Q2600/178

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Quick Facts

Patent No.: US 9,611,511
App. No.: 13/642,321
Granted: Apr 4, 2017
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to single polynucleotides or sets of polynucleotides for detecting single miRNAs or sets of miRNAs for diagnosing and/or prognosing of an acute coronary syndrome in a blood sample from a human. Further, the present invention relates to means for diagnosing and/or prognosing of an acute coronary syndrome comprising said polynucleotides or sets of polynucleotides. Furthermore, the present invention relates to a method for diagnosing and/or prognosing of an acute coronary syndrome based on the determination of expression profiles of single miRNAs or sets of miRNAs representative for an acute coronary syndrome compared to a reference. In addition, the present invention relates to a kit for diagnosing and/or prognosing of an acute coronary syndrome comprising means for determining expression profiles of single miRNAs or sets of miRNAs representative for an acute coronary syndrome and at least one reference.

Claims (336)

1. A method for detecting a decreased level of at least one miRNA in a human patient having, or suspected of having, an acute coronary syndrome comprising the steps of:

(i) providing a blood cell sample from a human, wherein the blood cell sample is a blood cellular fraction consisting of a mixture of erythrocytes, leukocytes and thrombocytes, and

(ii) detecting whether there is a decreased level of the at least one miRNA in the blood cell sample as compared to a control level of a healthy human subject, or a human subject not having or not being suspected of having an acute coronary syndrome, by contacting the sample with at least one probe for at least one down-regulated miRNA and detecting binding between the probe and the down-regulated miRNA;

wherein the nucleotide sequence of said at least one down-regulated miRNA is miR-455-3p having SEQ ID NO: 16, or sequence having at least 95% sequence identity thereto.

2. The method of claim 1 , wherein at least one additional nucleotide sequence of at least one additional down-regulated miRNA is detected, wherein the at least one additional down-regulated miRNA is selected from:

miR-193a-3p having SEQ ID NO: 255;

miR-636 having SEQ ID NO: 174;

miR-767-5p having SEQ ID NO: 19;

miR-345 having SEQ ID NO: 283;

miR-631 having SEQ ID NO: 259;

miR-7-1* having SEQ ID NO: 135;

miR-380* having SEQ ID NO: 32;

miR-20b* having SEQ ID NO: 22;

miR-330-3p having SEQ ID NO: 24;

miR-1254 having SEQ ID NO: 150;

miR-217 having SEQ ID NO: 157;

miR-146b-3p having SEQ ID NO: 123;

miR-151-5p having SEQ ID NO: 243;

miR-802 having SEQ ID NO: 52;

miR-497* having SEQ ID NO: 252;

miR-492 having SEQ ID NO: 184;

miR-566 having SEQ ID NO: 157;

miR1291 having SEQ ID NO: 1;

miR663b having SEQ ID NO:257; and,

miRNA sequences having at least 95% sequence identity thereto.

3. The method of claim 1 , wherein the method further comprises detecting whether there is an increased level of at least one up-regulated miRNA in the blood cell sample as compared to a control level by contacting the sample with at least one probe for at least one up-regulated miRNA and detecting binding between the probe and the up-regulated miRNA, wherein the at least one up-regulated miRNA is selected from:

miR-142-5p having SEQ ID NO: 162,

miR-23b* having SEQ ID NO:68,

miR-1250 having SEQ ID NO:70,

miR-920 having SEQ ID NO:137,

miR-1281 having SEQ ID NO:62,

miR-892b having SEQ ID NO: 15,

miR-135* having SEQ ID NO:95,

miR-93 having SEQ ID NO:20,

miR-615-5p having SEQ ID NO:266,

miR-624 having SEQ ID NO:232,

miR-30e having SEQ ID NO:55,

miR-140-5p having SEQ ID NO:85,

miR-200b* having SEQ ID NO:261,

miR-193b having SEQ ID NO:267,

miR-1304 having SEQ ID NO:148,

miR-409-3p having SEQ ID NO:215,

miR-134 having SEQ ID NO:256,

miR-194* having SEQ ID NO:272,

miR-877* having SEQ ID NO:268,

miR-1303 having SEQ ID NO:84, and,

miRNA sequences having at least 95% sequence identity thereto.

4. The method of claim 1 , wherein step (ii) is determined using reverse-transcribed miRNA.

5. The method of claim 1 , wherein step (ii) is determined using a quantitative real-time PCR machine by reverse-transcribing the total RNA into cDNA, and amplifying the cDNA and thereby quantifying said miRNA(s).

6. The method of claim 1 , wherein the acute coronary syndrome is acute myocardial infarction (AMI).

7. The method of claim 1 , further comprising detecting a deregulated level of at least one additional miRNA, wherein the deregulation comprises an up-regulation or a down-regulation of said at least one additional miRNA, and

wherein the at least one additional miRNAs are selected from the following sets:

Set No.

SEQ ID NO:

miRNAs

327

SEQ ID NO: 16, 253, 174

hsa-miR-455-3p, hsa-miR-345, hsa-miR-636

328

SEQ ID NO: 162, 16, 150

hsa-miR-142-5p, hsa-miR-455-3p, hsa-miR-1254

SEQ ID NO: 162, 16

hsa-miR-142-5p, hsa-miR-455-3p

338

SEQ ID NO: 243, 16, 32

hsa-miR-151-5p, hsa-miR-455-3p, hsa-miR-380*

348

SEQ ID NO: 184, 243, 16

hsa-miR-492, hsa-miR-151-5p, hsa-miR-455-3p

SEQ ID NO: 243, 16

hsa-miR-151-5p, hsa-miR-455-3p

357

SEQ ID NO: 243, 16, 70

hsa-miR-151-5p, hsa-miR-455-3p, hsa-miR-1250

361

SEQ ID NO: 162, 252, 16

hsa-miR-142-5p, hsa-miR-497*, hsa-miR-455-3p

1005

SEQ ID NO: 162, 157,

hsa-miR-142-5p, hsa-miR-566, hsa-miR-498, hsa-miR-

234, 184, 68, 16, 70, 252,

492, hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-1250,

52, 15, 243, 62, 123, 95,

hsa-miR-497*, hsa-miR-802, hsa-miR-8926, hsa-miR-

150, 22, 32, 259, 253, 31

151-5p, hsa-miR-1281, hsa-miR-1466-3p, hsa-miR-

135b*, hsa-miR-1254, hsa-miR-20b*, hsa-miR-380*,

hsa-miR-631, hsa-miR-345, hsa-miR-139-5p

383

SEQ ID NO: 62, 16, 253

hsa-miR-1281, hsa-miR-455-3p, hsa-miR-345

381

SEQ ID NO: 184, 52, 16

hsa-miR-492, hsa-miR-802, hsa-miR-455-3p

389

SEQ ID NO: 243, 68, 16

hsa-miR-151-5p, hsa-miR-23b*, hsa-miR-455-3p

397

SEQ ID NO: 16, 150, 174

hsa-miR-455-3p, hsa-miR-1254, hsa-miR-636

402

SEQ ID NO: 68, 16, 137

hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-920

404

SEQ ID NO: 234, 184, 16

hsa-miR-498, hsa-miR-492, hsa-miR-455-3p

406

SEQ ID NO: 234, 68, 16

hsa-miR-498, hsa-miR-23b*, hsa-miR-455-3p

421

SEQ ID NO: 162, 62, 16

hsa-miR-142-5p, hsa-miR-1281, hsa-miR-455-3p

424

SEQ ID NO: 217, 62, 16

hsa-miR-148b, hsa-miR-1281, hsa-miR-455-3p

429

SEQ ID NO: 157, 68, 16

hsa-miR-566, hsa-miR-23b*, hsa-miR-455-3p

439

SEQ ID NO: 68, 16, 252

hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-497*

441

SEQ ID NO: 16, 137, 52

hsa-miR-455-3p, hsa-miR-920, hsa-miR-802

451

SEQ ID NO: 157, 234, 16

hsa-miR-566, hsa-miR-498, hsa-miR-455-3p

454

SEQ ID NO: 52, 243, 16

hsa-miR-802, hsa-miR-151-5p, hsa-miR-455-3p

463

SEQ ID NO: 22, 135, 16

hsa-miR-20b*, hsa-miR-7-1*, hsa-miR-455-3p

464

SEQ ID NO: 68, 16, 259

hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-631

SEQ ID NO: 52, 16

hsa-miR-802, hsa-miR-455-3p

474

SEQ ID NO: 157, 184, 16

hsa-miR-566, hsa-miR-492, hsa-miR-455-3p

487

SEQ ID NO: 252, 16, 253

hsa-miR-497*, hsa-miR-455-3p, hsa-miR-345

499

SEQ ID NO: 62, 16, 174

hsa-miR-1281, hsa-miR-455-3p, hsa-miR-636

515

SEQ ID NO: 62, 16, 150

hsa-miR-1281, hsa-miR-455-3p, hsa-miR-1254

514

SEQ ID NO: 52, 68, 16

hsa-miR-802, hsa-miR-23b*, hsa-miR-455-3p

533

SEQ ID NO: 22, 19, 16

hsa-miR-20b*, hsa-miR-767-5p, hsa-miR-455-3p

539

SEQ ID NO: 52, 16, 70

hsa-miR-802, hsa-miR-455-3p, hsa-miR-1250

543

SEQ ID NO: 116, 62, 16

hsa-miR-339-3p, hsa-miR-1281, hsa-miR-455-3p

SEQ ID NO: 68, 16

hsa-miR-23b*, hsa-miR-455-3p

554

SEQ ID NO: 135, 31, 16

hsa-miR-7-1*, hsa-miR-139-5p, hsa-miR-455-3p

551

SEQ ID NO: 68, 16, 70

hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-1250

SEQ ID NO: 62, 16

hsa-miR-1281, hsa-miR-455-3p

556

SEQ ID NO: 16, 150, 135

hsa-miR-455-3p, hsa-miR-1254, hsa-miR-7-1*

567

SEQ ID NO: 184, 16, 252

hsa-miR-492, hsa-miR-455-3p, hsa-miR-497*

566

SEQ ID NO: 184, 16, 70

hsa-miR-492, hsa-miR-455-3p, hsa-miR-1250

563

SEQ ID NO: 184, 68, 16

hsa-miR-492, hsa-miR-23b*, hsa-miR-455-3p

586

SEQ ID NO: 252, 62, 16

hsa-miR-497*, hsa-miR-1281, hsa-miR-455-3p

595

SEQ ID NO: 135, 19, 16

hsa-miR-7-1*, hsa-miR-767-5p, hsa-miR-455-3p

602

SEQ ID NO: 16, 252, 52

hsa-miR-455-3p, hsa-miR-497*, hsa-miR-802

603

SEQ ID NO: 234, 16, 70

hsa-miR-498, hsa-miR-455-3p, hsa-miR-1250

607

SEQ ID NO: 22, 31, 16

hsa-miR-20b*, hsa-miR-139-5p, hsa-miR-455-3p

612

SEQ ID NO: 135, 16, 32

hsa-miR-7-1*, hsa-miR-455-3p, hsa-miR-380*

SEQ ID NO: 16, 253

hsa-miR-455-3p, hsa-miR-345

SEQ ID NO: 184, 16

hsa-miR-492, hsa-miR-455-3p

661

SEQ ID NO: 16, 174, 135

hsa-miR-455-3p, hsa-miR-636, hsa-miR-7-1*

664

SEQ ID NO: 16, 32, 252

hsa-miR-455-3p, hsa-miR-380*, hsa-miR-497*

100

SEQ ID NO: 234, 16

hsa-miR-498, hsa-miR-455-3p

675

SEQ ID NO: 252, 16, 150

hsa-miR-497*, hsa-miR-455-3p, hsa-miR-1254

677

SEQ ID NO: 16, 252, 137

hsa-miR-455-3p, hsa-miR-497*, hsa-miR-920

681

SEQ ID NO: 217, 116, 16

hsa-miR-148b, hsa-miR-339-3p, hsa-miR-455-3p

103

SEQ ID NO: 16, 32

hsa-miR-455-3p, hsa-miR-380*

693

SEQ ID NO: 16, 70, 137

hsa-miR-455-3p, hsa-miR-1250, hsa-miR-920

725

SEQ ID NO: 16, 32, 150

hsa-miR-455-3p, hsa-miR-380*, hsa-miR-1254

731

SEQ ID NO: 31, 16, 252

hsa-miR-139-5p, hsa-miR-455-3p, hsa-miR-497*

750

SEQ ID NO: 16, 70, 32

hsa-miR-455-3p, hsa-miR-1250, hsa-miR-380*

758

SEQ ID NO: 16, 150, 253

hsa-miR-455-3p, hsa-miR-1254, hsa-miR-345

760

SEQ ID NO: 68, 16, 32

hsa-miR-23b*, hsa-miR-455-3p, hsa-miR-380*

135

SEQ ID NO: 31, 16

hsa-miR-139-5p, hsa-miR-455-3p

145

SEQ ID NO: 16, 150

hsa-miR-455-3p, hsa-miR-1254

789

SEQ ID NO: 16, 253, 135

hsa-miR-455-3p, hsa-miR-345, hsa-miR-7-1*

793

SEQ ID NO: 16, 70, 252

hsa-miR-455-3p, hsa-miR-1250, hsa-miR-497*

802

SEQ ID NO: 19, 16, 32

hsa-miR-767-5p, hsa-miR-455-3p, hsa-miR-380*

800

SEQ ID NO: 19, 31, 16

hsa-miR-767-5p, hsa-miR-139-5p, hsa-miR-455-3p

804

SEQ ID NO: 116, 252, 16

hsa-miR-339-3p, hsa-miR-497*, hsa-miR-455-3p

803

SEQ ID NO: 16, 32, 259

hsa-miR-455-3p, hsa-miR-380*, hsa-miR-631

806

SEQ ID NO: 16, 259, 150

hsa-miR-455-3p, hsa-miR-631, hsa-miR-1254

159

SEQ ID NO: 16, 70

hsa-miR-455-3p, hsa-miR-1250

815

SEQ ID NO: 16, 70, 150

hsa-miR-455-3p, hsa-miR-1250, hsa-miR-1254

164

SEQ ID NO: 16, 174

hsa-miR-455-3p, hsa-miR-636

828

SEQ ID NO: 16, 32, 273

hsa-miR-455-3p, hsa-miR-380*, hsa-miR-194*

833

SEQ ID NO: 16,70, 259

hsa-miR-455-3p, hsa-miR-1250, hsa-miR-631

847

SEQ ID NO: 31, 16, 32

hsa-miR-139-5p, hsa-miR-455-3p, hsa-miR-380*

850

SEQ ID NO: 16, 32, 23

hsa-miR-455-3p, hsa-miR-380*, hsa-miR-491-3p

194

SEQ ID NO: 16, 252

hsa-miR-455-3p, hsa-miR-497*

875

SEQ ID NO: 31, 16, 273

hsa-miR-139-5p, hsa-miR-455-3p, hsa-miR-194*

881

SEQ ID NO: 16, 252, 23

hsa-miR-455-3p, hsa-miR-497*, hsa-miR-491-3p

202

SEQ ID NO: 135, 16

hsa-miR-7-1*, hsa-miR-455-3p

232

SEQ ID NO: 19, 16

hsa-miR-767-5p, hsa-miR-455-3p

237

SEQ ID NO: 16, 137

hsa-miR-455-3p, hsa-miR-920

239

SEQ ID NO: 116, 16

hsa-miR-339-3p, hsa-miR-455-3p

916

SEQ ID NO: 16, 273, 252

hsa-miR-455-3p, hsa-miR-194*, hsa-miR-497*

249

SEQ ID NO: 16, 273

hsa-miR-455-3p, hsa-miR-194*

931

SEQ ID NO: 16, 273, 23

hsa-miR-455-3p, hsa-miR-194*, hsa-miR-491-3p

263

SEQ ID NO: 16, 259

hsa-miR-455-3p, hsa-miR-631

957

SEQ ID NO: 19, 16, 273

hsa-miR-767-5p, hsa-miR-455-3p, hsa-miR-194*.

Assignments (2)

CHANGE OF NAME Recorded Jun 21, 2017

From: COMPREHENSIVE BIOMARKER CENTER GMBH

To: HUMMINGBIRD DIAGNOSTICS GMBH

Reel/Frame 042928/0606 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 14, 2014

From: FEBIT HOLDING GMBH

To: COMPREHENSIVE BIOMARKER CENTER GMBH

Reel/Frame 031962/0001 →

Priority Claims (2)

EP 10004190 · Apr 20, 2010 · regional

EP 10185136 · Oct 1, 2010 · regional

Continuity (2)

Provisional Application 61326043 · Apr 20, 2010

Related Publication 20130157883A1 · Jun 20, 2013