# US 2013/0157883 A1 · Complex miRNA Sets as Novel Biomarkers for an Acute Coronary Syndrome

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- Number: US 2013/0157883 A1
- Document ID: US20130157883A1
- Status: Published application
- Kind: A1
- Application number: 13/642,321
- Filed: 2011-04-19
- Published: 2013-06-20
- Earliest claimed: 2010-04-20
- Assignees: Febit Holding GmbH
- Inventors: Andreas Keller; Peer F. Stähler; Markus Beier; Benjamin Meder; Hugo A. Katus; Wolfgang Rottbauer
- Web page: https://patentgrep.com/patent/US20130157883A1

## CPC

- C12Q 1/6876: Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/158: Expression markers
- C12Q 2600/178: miRNA, siRNA or ncRNA
- Y02A 90/10: Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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

### Claim 1

A polynucleotide for detecting a miRNA or a set comprising at least two polynucleotides for detecting a set comprising at least two miRNAs for diagnosing and/or prognosing of an acute coronary syndrome in a blood sample from a human, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 283.

### Claim 2 (depends on 1)

The polynucleotide or set comprising polynucleotides of claim 1, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: Ito SEQ ID NO: 153.

### Claim 3 (depends on 1)

The polynucleotide or set comprising polynucleotides of claim 1, wherein
(i) the polynucleotide is complementary to the miRNA according to claim 1, or the polynucleotides comprised in the set are complementary to the miRNAs comprised in the set according to claim 1,
(ii) the polynucleotide is a fragment of the polynucleotide according to (i), or the polynucleotides comprised in the set are fragments of the polynucleotides comprised in the set according to (i), or
(iii) the polynucleotide has at least 80% sequence identity to the polynucleotide sequence of the polynucleotide according to (i) or polynucleotide fragment according to (ii), or the polynucleotides comprised in the set have at least 80% sequence identity to the polynucleotide sequences of the polynucleotides comprised in the set according to (i) or polynucleotide fragments comprised in the set according to (ii).

### Claim at position 4

-6. (canceled)

### Claim 7 (depends on 2)

The set comprising polynucleotides of claim 2, wherein said polynucleotides are for detecting a set comprising at least one further miRNA, wherein the nucleotide sequence of said miRNA is selected from the group consisting of SEQ ID NO: 154 to SEQ ID NO: 241.

### Claim 8 (depends on 1)

The set comprising polynucleotides of claim 1, wherein the nucleotide sequences of said miRNAs are selected from one or more sets listed in FIG. 28 and/or FIG. 30.

### Claim at position 7

-10. (canceled)

### Claim 11

A method for diagnosing and/or prognosing of an acute coronary syndrome comprising the steps of:
(i) determining an expression profile of a miRNA or a set comprising at least two miRNAs representative for an acute coronary syndrome in a blood sample from a human, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 283, a fragment thereof, and a sequence having at least 80% sequence identity thereto, and
(ii) comparing said expression profile to a reference, wherein the comparison of said expression profile to said reference allows for the diagnosis and/or prognosis of an acute coronary syndrome and/or applying an algorithm or a mathematical function to said expression profile, wherein the application of said algorithm or mathematical function to said expression profile allows for the diagnosis and/or prognosis of an acute coronary syndrome.

### Claim 12 (depends on 11)

The method of claim 11, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 153, a fragment thereof, and a sequence having at least 80% sequence identity thereto.

### Claim 13 (depends on 11)

The method of claim 11, wherein the algorithm or mathematical function is obtained from a reference expression profile of at least one subject with one known clinical condition which is an acute coronary syndrome, or which is no acute coronary syndrome, wherein the reference expression profile is the profile of a miRNA that has a nucleotide sequence that corresponds to the nucleotide sequence of the miRNA of step (i) or is the profile of a set comprising at least two miRNAs that have nucleotide sequences that correspond to the nucleotide sequences of the miRNAs of step (i).

### Claim 14 (depends on 11)

The method of claim 11, wherein the algorithm or mathematical function is obtained from reference expression profiles of at least two subjects with at least two known clinical conditions which are an acute coronary syndrome and any other known clinical condition(s), wherein the reference expression profiles are the profiles of a miRNA that has a nucleotide sequence that corresponds to the nucleotide sequence of the miRNA of step (i) or are the profiles of a set comprising at least two miRNAs that have nucleotide sequences that correspond to the nucleotide sequences of the miRNAs of step (i).

### Claim 15 (depends on 14)

The method of claim 14, wherein the two known clinical conditions are an acute coronary syndrome and no acute coronary syndrome.

### Claim 16 (depends on 11)

The method of claim 11, wherein the algorithm or mathematical function is obtained using a machine learning approach.

### Claim 17 (depends on 16)

The method of claim 16, wherein the machine learning approach involves the following steps:
(i) inputting the reference expression profile(s) of (a) subject(s) with the known clinical condition of an acute coronary syndrome and/or with any other known clinical condition(s), preferably with the known clinical condition of no acute coronary syndrome, and
(ii) computing an algorithm or a mathematical function based on said reference expression profile(s) that is suitable to distinguish between the (likely) clinical condition of an acute coronary syndrome and any other (likely) clinical condition(s), preferably the clinical condition of no acute coronary syndrome, or to decide if the clinical condition of an acute coronary syndrome or no acute coronary syndrome is present or will likely be present in said human, particularly human patient.

### Claim 18 (depends on 11)

The method of claim 11, wherein the reference is a reference expression profile of at least one subject with one known clinical condition which is an acute coronary syndrome, or which is no acute coronary syndrome, wherein the reference expression profile is the profile of a miRNA that has a nucleotide sequence that corresponds to the nucleotide sequence of the miRNA of step (i) or is the profile of a set comprising at least two miRNAs that have nucleotide sequences that correspond to the nucleotide sequences of the miRNAs of step (i).

### Claim at position 16

-21. (canceled)

### Claim 22 (depends on 12)

The method of claim 12, wherein the set comprises at least one further miRNA, wherein the nucleotide sequence of said miRNA is selected from the group consisting of SEQ ID NO: 154 to SEQ ID NO: 241, a fragment thereof, and a sequence having at least 80% sequence identity thereto.

### Claim 23 (depends on 11)

The method of claim 11, wherein the nucleotide sequences of said miRNAs are selected from one or more sets listed in FIG. 28 and/or FIG.

### Claim at position 19

-26. (canceled)

### Claim 27 (depends on 11)

The method of claim 11, wherein the blood sample is a whole blood sample, or a blood fraction sample, preferably a blood plasma sample, a blood serum sample, or a sample of blood cells, wherein the blood cells are preferably erythrocytes, leukocytes, and/or thrombocytes.

### Claim at position 21

-32. (canceled)

### Claim 33 (depends on 1)

Means for diagnosing and/or prognosing of an acute coronary syndrome comprising a polynucleotide or a set comprising at least two polynucleotides according to claim 1.

### Claim 34

(canceled)

### Claim 35

A kit for diagnosing and/or prognosing of an acute coronary syndrome comprising
(i) means for determining an expression profile of a miRNA or a set comprising at least two miRNAs representative for an acute coronary syndrome in a blood sample from a human, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 283, a fragment thereof, and a sequence having at least 80% sequence identity thereto; and
(ii) at least one reference and/or algorithm or mathematical function.

### Claim 36 (depends on 35)

The kit of claim 35, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 153, a fragment thereof, and a sequence having at least 80% sequence identity thereto.

### Claim 37 (depends on 36)

The kit of claim 36, wherein the set comprises at least one further miRNA, wherein the nucleotide sequence of said miRNA is selected from the group consisting of SEQ ID NO: 154 to SEQ ID NO: 241, a fragment thereof, and a sequence having at least 80% sequence identity thereto.

### Claim 38 (depends on 37)

The kit of claim 37, wherein the nucleotide sequences of said miRNAs are selected from one or more sets listed in FIG. 28 and/or FIG. 30.

### Claim 39

(canceled)

### Claim 40

A polynucleotide for detecting a miRNA or a set comprising at least two polynucleotides for detecting a set comprising at least two miRNAs for predicting, estimating and/or determining the heart infarct size, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 181 (hsa-miR-145), SEQ ID NO: 240 (hsa-miR-223), and SEQ ID NO: 241 (hsa-miR-30c).

### Claim 41

A miRNA or a set comprising at least two miRNAs as biomarker(s) for the diagnosis and/or prognosis of an acute coronary syndrome, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to 283.

### Claim 42 (depends on 41)

The miRNA or miRNA set of claim 41, wherein the nucleotide sequence of said miRNA or the nucleotide sequences of said miRNAs is (are) selected from the group consisting of SEQ ID NO: 1 to 153.

### Claim 43 (depends on 42)

The miRNA set of claim 42, wherein the miRNA set comprises at least one further miRNA, wherein the nucleotide sequence of said miRNA is selected from the group consisting of SEQ ID NO: 154 to 241.

### Claim 44 (depends on 41)

The miRNA set of claim 41, wherein the nucleotide sequences of said miRNAs are selected from one or more sets listed in FIG. 28 and/or FIG. 30.

### Claim 45 (depends on 41)

The miRNA set of claim 41, wherein the blood sample is a whole blood sample or a blood fraction sample, preferably a blood plasma sample, a blood serum sample, or a sample of blood cells, wherein the blood cells are preferably erythrocytes, leukocytes, and/or thrombocytes.

### Claim 46 (depends on 1)

The polynucleotide or set comprising polynucleotides of claim 1, wherein the blood sample is a whole blood sample or a blood fraction sample, preferably a blood plasma sample, a blood serum sample, or a sample of blood cells, wherein the blood cells are preferably erythrocytes, leukocytes, and/or thrombocytes.