# US 11,441,181 B2 · miRNA-124 as a biomarker

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- Number: US 11,441,181 B2
- Document ID: US11441181B2
- Status: Granted
- Kind: B2
- Application number: 14/761,674
- Filed: 2014-01-17
- Published: 2015-12-17
- Granted: 2022-09-13
- Earliest claimed: 2013-01-17
- Assignees: Abivax; Centre National de la Recherche; Universite De Montpellier; Institut Curie
- Applicants: Abivax; Centre National De La Recherche Scientifique; Universite De Montpellier; Institut Curie
- Inventors: Jamal Tazi; Didier Scherrer; Aude Garcel; Noëlie Campos; Romain Najman; Florence Mahuteau-Betzer
- Web page: https://patentgrep.com/patent/US11441181B2

## CPC

- C12Q 1/6876: Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q 1/70: involving virus or bacteriophage {(immunoassay for viruses G01N33/56983)}
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/158: Expression markers
- C12Q 2600/178: miRNA, siRNA or ncRNA
- 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

## Abstract

A use of at least one miRNA, said at least one miRNA being miR-124, as a biomarker, in particular of a viral infection, or of an efficacy of a therapeutic treatment of said viral infection.

## Claims

### Claim 1

An in vitro or ex vivo method of measuring miR-124 in a patient with a HIV infection, comprising at least the steps of:
a. obtaining a biological sample from said patient, said biological sample selected from the group consisting of: a whole blood sample, a swab sample, a plasma sample, a serum sample, a saliva sample, a vaginal fluid sample, a sperm sample, a pharyngeal fluid sample, a bronchial fluid sample, a fecal fluid sample, and a lacrymal fluid sample; and
b. measuring a presence or expression level of at least miR-124 in the biological sample from said patient,
wherein measuring the presence or expression level of miR-124 comprises contacting the biological sample with a nucleic acid probe able to specifically hybridize to miR-124, and detecting the hybridization of said probe to miR-124,
wherein said nucleic acid probe includes a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 6 to 86.

### Claim 2 (depends on 1)

The method of claim 1, wherein said biological sample is selected from the group consisting of: a whole blood sample, a plasma sample, and a serum sample.

### Claim 3

An in vitro or ex vivo method of assessing an activity of a quinoline derivative of formula (I) or (II) or one of their pharmaceutically acceptable salts, for preventing and/or treating a HIV infection in a patient treated with said quinoline derivative, comprising at least the steps of:
a. measuring a presence or an expression level of at least one miRNA, including miR-124, in a first biological sample previously obtained from said patient before administering said quinoline derivative and in a second biological sample previously obtained from said patient after administering said quinoline derivative; and
b. determining if said presence or expression level is modulated in the second biological sample obtained after the treatment as compared to the first biological sample obtained before the treatment;
wherein a modulated presence or expression level of said miRNA is indicative of an activity of said quinoline derivative;
wherein formula (I) is:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —NR1R2 group in which R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group,
a (C1-C3) fluoroalkoxy group,
a —NO2 group,
a phenoxy group, or
a (C1-C4) alkoxy group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group; and
wherein formula (II) is:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —CN group,
a hydroxyl group,
a —COOR1 group,
a (C1-C3) fluoroalkyl group,
a —NO2 group,
a —NR1R2 group, or
a (C1-C4) alkoxy group;
R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group.

### Claim 4 (depends on 3)

The method of claim 3, wherein said biological sample is selected from the group consisting of a biological tissue sample, a whole blood sample, a swab sample, a plasma sample, a serum sample, a saliva sample, a vaginal fluid sample, a sperm sample, a pharyngeal fluid sample, a bronchial fluid sample, a fecal fluid sample, a cerebrospinal fluid sample, a lacrymal fluid sample, and a tissue culture supernatant sample.

### Claim 5 (depends on 3)

The method of claim 3, wherein said patient is tested at a time interval selected from the group consisting of hourly, twice a day, daily, twice a week, weekly, twice a month, monthly, twice a year, yearly, and every other year.

### Claim 6 (depends on 3)

The method of claim 3, wherein the quinoline derivative is represented by formula (I) or one of its pharmaceutically acceptable salts where:
n is 1;
R is a (C1-C3) fluoroalkoxy group; and
R′ and R″ are each a hydrogen atom.

### Claim 7 (depends on 6)

The method of claim 6, wherein the quinoline derivative is 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine.

### Claim 8 (depends on 3)

The method of claim 3, wherein the quinoline derivative is represented by formula (II) or one of its pharmaceutically acceptable salts where:
n is 1;
R is a (C1-C3) fluoroalkoxy group; and
R′ and R″ are each a hydrogen atom.

### Claim 9 (depends on 8)

The method of claim 8, wherein the quinoline derivative is 8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine.

### Claim 10 (depends on 3)

The method of claim 3, wherein the quinoline derivative is represented by formula (I) or one of its pharmaceutically acceptable salts.

### Claim 11 (depends on 3)

The method of claim 3, wherein the quinoline derivative is represented by formula (II) or one of its pharmaceutically acceptable salts.

### Claim 12

An in vitro or ex vivo method for measuring miRNA expressed by one or more cells treated with a candidate compound presumed effective in preventing and/or treating a HIV infection, comprising at least the steps of:
a. treating at least one isolated cell able to express at least one miRNA, the at least one miRNA being miR-124, with said candidate compound, said cell being under conditions suitable for expressing said at least one miRNA; and
b. measuring a presence or expression level of said at least one miRNA;
wherein said candidate compound is a quinoline derivative represented by formula (I) or one of its pharmaceutically acceptable salts:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —NR1R2 group in which R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group,
a (C1-C3) fluoroalkoxy group,
a —NO2 group,
a phenoxy group, or
a (C1-C4) alkoxy group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group;
or wherein said candidate compound is a quinoline derivative represented by formula (II) or one of its pharmaceutically acceptable salts:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —CN group,
a hydroxyl group,
a —COOR1 group,
a (C1-C3) fluoroalkyl group,
a —NO2 group,
a —NR1R2 group, or
a (C1-C4) alkoxy group;
R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group.

### Claim 13 (depends on 12)

The method of claim 12, further comprising:
c. comparing said measured presence or expression level with a measure or expression level of said at least one miRNA in an untreated isolated cell, wherein:
a modulated presence or expression level of said miRNA is indicative of the efficacy of said candidate compound on a HIV infection; and
said candidate compound is:
(i) a quinoline derivative represented by formula (I) or one of its pharmaceutically acceptable salts:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —NR1R2 group in which R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group,
a (C1-C3) fluoroalkoxy group,
a —NO2 group,
a phenoxy group, or
a (C1-C4) alkoxy group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group; or
(ii) a quinoline derivative represented by formula (II) or one of its pharmaceutically acceptable salts:
where:
n is 1 or 2;
R independently represents:
a hydrogen atom,
a halogen atom,
a (C1-C3) alkyl group,
a —CN group,
a hydroxyl group,
a —COOR1 group,
a (C1-C3) fluoroalkyl group,
a —NO2 group,
a —NR1R2 group, or
a (C1-C4) alkoxy group;
R1 and R2 are independently a hydrogen atom or a (C1-C3) alkyl group;
R′ is a hydrogen atom, a halogen atom, a (C1-C4) alkyl group, or a (C1-C4) alkoxy group; and
R″ is a hydrogen atom or a (C1-C4) alkyl group.

### Claim 14

An in vitro or ex vivo method for measuring miRNA expressed by one or more cells treated with a candidate compound presumed effective in treating a HIV infection, comprising at least the steps of:
a. treating at least one isolated cell able to express at least one miRNA, the at least one miRNA being miR-124, with said candidate compound, said cell being under conditions suitable for expressing said at least one miRNA; and
b. measuring a presence or expression level of said at least one miRNA.