# US 11,998,331 B2 · Use of micro-ribonucleic acid (miRNA) to diagnose transplant rejection and tolerance of immunosuppression therapy

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- Number: US 11,998,331 B2
- Document ID: US11998331B2
- Status: Granted
- Kind: B2
- Application number: 16/365,194
- Filed: 2019-03-26
- Published: 2019-10-17
- Granted: 2024-06-04
- Earliest claimed: 2014-04-10
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: Abraham Shaked; Bao-Li Chang; Brendan Keating; Toumy Guettouche
- Web page: https://patentgrep.com/patent/US11998331B2

## CPC

- A61B 5/15: Devices for taking samples of blood
- A61B 10/0038: {Devices for taking faeces samples; Faecal examination devices (anal receptacles A61F5/451)}
- A61B 10/007: {for taking urine samples (measuring urological functions A61B5/20; genital receptacles A61F5/451; urinals for bed-ridden persons A61G9/006)}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- G16B 25/00: ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B 25/10: Gene or protein expression profiling; Expression-ratio estimation or normalisation
- G16B 25/20: Polymerase chain reaction [PCR]; Primer or probe design; Probe optimisation
- G16H 50/50: for simulation or modelling of medical disorders
- A61B 5/150015: {Source of blood}
- A61B 2010/0061: {Alimentary tract secretions, e.g. biliary, gastric, intestinal, pancreatic secretions}
- C12Q 2600/158: Expression markers
- C12Q 2600/178: miRNA, siRNA or ncRNA
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA

## Abstract

The present invention relates to the discovery that the expression levels of some microRNAs (miRNAs) can use a diagnostic signature to predict transplant outcomes in a transplant recipient. Thus, in various embodiments described herein, the methods of the invention relate to methods of diagnosing a transplant subject for acute rejection such as acute cellular rejection (ACR), methods of predicting a subject's risk of having or developing ACR and methods of assessing in a subject the likelihood of a successful or failure minimization of immunosuppression therapy (IST) dosage from standard ranges.

## Claims

### Claim 1

A method for detecting or predicting transplant rejection of a transplanted liver in a subject being administered a dose of an immunosuppressant, the method comprising:
i) determining a level of expression of hsa-miR-483-5p (SEQ ID NO: 3), hsa-miR-885-5p (SEQ ID NO: 4) and hsa-miR-122-5p (SEQ ID NO: 5) in a sample from the subject wherein the sample is selected from the group consisting of blood, plasma and serum;
ii) comparing the level of expression of hsa-miR-483-5p (SEQ ID NO: 3), hsa-miR-885-5p (SEQ ID NO: 4) and hsa-miR-122-5p (SEQ ID NO: 5) in the sample from the subject relative to a baseline level in a control wherein an increase in the level of expression in the sample from the level of the at least one miRNA in the control is indicative of an acute transplant rejection;
iii) wherein when acute transplant rejection is indicated, the rejection is treated by increasing the dose of the immunosuppressant; and
iv) wherein when acute transplant rejection is not indicated in step ii., decreasing or minimizing the dose of the immunosuppressant.

### Claim 2 (depends on 1)

The method of claim 1, wherein the acute transplant rejection comprises acute cellular rejection (ACR).

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject is a mammal.

### Claim 4 (depends on 3)

The method of claim 3, wherein the mammal is a human.

### Claim 5 (depends on 1)

The method of claim 1, wherein the level of expression in the sample is higher than the level in the control by at least 1 fold.

### Claim 6 (depends on 1)

The method of claim 1, wherein the comparison of the level of miRNA expression in a sample relative to the baseline level is computed in a regression model to indicate a trajectory of acute rejection of the transplanted organ.

### Claim 7 (depends on 1)

The method of claim 1, further comprising the step of repeating steps i. to iii.