# US 12,760,368 B2 · Circular RNAs for diagnosis of depression and prediction of response to antidepressant treatment

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- Number: US 12,760,368 B2
- Document ID: US12760368B2
- Status: Granted
- Kind: B2
- Application number: 18/547,830
- Filed: 2022-02-25
- Published: 2024-06-20
- Granted: 2026-10-13
- Earliest claimed: 2021-02-26
- Assignees: UNM Rainforest Innovations; Board of Regents, The University of Texas System
- Applicants: UNM Rainforest Innovations; The Board of Regents of the University of Texas System
- Inventors: Nikolaos Mellios; Madhukar H. Trivedi
- Web page: https://patentgrep.com/patent/US12760368B2

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/118: Prognosis of disease development
- 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 plurality of circular RNAs (circRNAs) the expression of which is correlated with diagnosis for Major Depressive Disorder (MDD) and Bipolar Disorder (BD) and response to treatment with various antidepressants is provided. The circRNAs are useful for compositions, kits, assays, and methods for the identification, diagnosis, screening, treatment, and/or monitoring of brain disorders such as MDD and BD.

## Claims

### Claim 1

A method for assessing major depressive disorder (MDD) or bipolar disorder (BD) in a subject comprising:
obtaining a first sample from the subject;
assaying the first sample using probes and/or primers configured to identify the presence of and/or amplify one or more brain disorder-associated circRNA biomarkers;
producing an expression profile of the one or more brain disorder-associated circRNA biomarkers based on the assay;
comparing the expression profile to a control expression profile or to an expression profile from a second sample obtained from the subject after administration of an antidepressant treatment;
and administering, changing, or discontinuing an antidepressant therapy for said subject based on the differential expression of said brain disorder-associated circRNA biomarkers in said first sample compared to said control or to said second sample;
and wherein the antidepressant therapy is selected from: administering a Selective Serotonin Reuptake Inhibitors (SSRIs), administering a serotonin and norepinephrine reuptake inhibitors (SNRIs), administering a Monoamine oxidase inhibitors (MAOIs), or any combination thereof;
and wherein the brain disorder-associated circRNA biomarkers comprise one or more circRNAs selected from SEQ ID NOs: 1-45 or 47-241.

### Claim 2 (depends on 1)

The method of claim 1, wherein said first and/or second sample comprises a physiological fluid sample.

### Claim 3 (depends on 2)

The method of claim 2, wherein said physiological fluid sample comprises blood, cell, or tissue sample.

### Claim 4 (depends on 1)

The method of claim 1, wherein said subject is a human.

### Claim 5 (depends on 1)

The method of claim 1, wherein the primers include a sequence that spans a splice junction of any of the one or more brain disorder-associated circRNA biomarkers in an asymmetric manner.

### Claim 6 (depends on 1)

The method of claim 1, wherein one or more of the primers comprises a PCR primer sequence selected from the group of sequences according to SEQ ID NOs: 242-283 or 286-433, or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% nucleic acid sequence identity thereto, or to the complement thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the circRNA biomarkers are selected from: circCDR1as, circTULP4, circCHIC1, circMIR5695, circRALGAPB, circCOMT, circPICALM, circDDX50, circRERE, or circSATB2, circICAM1, circDDR1, circMALAT1, circHMGA2, circCYP24A1, circDLG5, circMYO9B, circNFATC3, circDUSP22, circFKBP8, circVDAC2, or circTRIM69, or any combination thereof.

### Claim 8 (depends on 1)

The method of claim 1, further comprising administering a tricyclic antidepressant.

### Claim 9

A method for assessing MDD or BD in a subject comprising:
providing a sample from the subject;
assaying the sample using primers configured to identify the presence of and/or amplify one or more brain disorder-associated circRNA biomarkers;
and determining whether the sample has altered levels of the one or more brain disorder-associated circRNAs, or a different expression profile of the one or more brain disorder-associated circRNAs, relative to a control representing levels of the one or more brain disorder-associated circRNAs, or an expression profile of the one or more brain disorder-associated circRNAs, in non-MDD or non-BD humans,
wherein the primers include a sequence that spans a splice junction of any of the one or more brain disorder-associated circRNA biomarkers in an asymmetric manner,
wherein the brain disorder-associated circRNA biomarkers comprise one or more circRNAs selected from SEQ ID NOs: 1-45 or 47-241.

### Claim 10 (depends on 9)

The method of claim 9, wherein said sample comprises a physiological fluid sample.

### Claim 11 (depends on 10)

The method of claim 10, wherein said physiological fluid sample comprises blood, cell, or tissue sample.

### Claim 12 (depends on 9)

The method of claim 9, wherein said subject is a human.

### Claim 13 (depends on 9)

The method of claim 9, wherein one or more of the primers comprises a PCR primer sequence selected from the group of sequences according to SEQ ID NOs: 242-283 or 286-433, or a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% nucleic acid sequence identity thereto, or to the complement thereof.

### Claim 14 (depends on 9)

The method of claim 9, wherein the circRNA biomarkers are selected from: circCDR1as, circTULP4, circCHIC1, circMIR5695, circRALGAPB, circCOMT, circPICALM, circDDX50, circRERE, or circSATB2, circICAM1, circDDR1, circMALAT1, circHMGA2, circCYP24A1, circDLG5, circMYO9B, circNFATC3, circDUSP22, circFKBP8, circVDAC2, or circTRIM69, or any combination thereof.

### Claim 15

A method of treating a MDD or BD condition in a patient who is predicted to benefit or not to benefit from therapeutic administration of an antidepressant treatment comprising:
detecting in a first sample of the patient the expression levels of one or more MDD/BD or antidepressant response/treatment-associated circRNA biomarkers to establish an expression profile of said patient;
administering to said patient an antidepressant treatment to treat MDD or BD wherein the antidepressant treatment medication is selected from the group consisting of: Selective Serotonin Reuptake Inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), Monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants;
detecting in a second sample of said patient the expression levels of said MDD- or BD-associated circRNA biomarkers after administration of said antidepressant treatment; and
correlating the levels of expression in said first and second samples to determine if the antidepressant treatment is effective at treating the condition, and continuing to administer the antidepressant treatment to treat MDD or BD based on said correlation, or stopping administering the antidepressant treatment to treat MDD or BD, or administering a different antidepressant treatment to treat MDD or BD,
wherein the circRNA biomarkers comprise one or more circRNAs selected from SEQ ID NOs: 1-45 or 47-241.

### Claim 16 (depends on 15)

The method of claim 15, wherein said first and/or second sample comprises a physiological fluid sample.

### Claim 17 (depends on 16)

The method of claim 16, wherein said physiological fluid sample comprises blood, cell, or tissue sample.

### Claim 18 (depends on 15)

The method of claim 15, wherein said patient is a human.

### Claim 19 (depends on 15)

The method of claim 15, wherein the circRNA biomarkers are selected from the group consisting of: circCDR1as, circTULP4, circCHIC1, circMIR5695, circRALGAPB, circCOMT, circPICALM, circDDX50, circRERE, or circSATB2, circICAM1, circDDR1, circMALAT1, circHMGA2, circCYP24A1, circDLG5, circMYO9B, circNFATC3, circDUSP22, circFKBP8, circ VDAC2, and circTRIM69.