Use of micro-ribonucleic acid (MIRNA) to diagnose transplant rejection and tolerance of immunosuppression therapy

a technology of immunosuppression therapy and microribonucleic acid, which is applied in the field of use of microribonucleic acid (mirna) to diagnose transplant rejection and tolerance of immunosuppression therapy, can solve the problems of graft loss, high invasiveness of allograft biopsies, and limited diagnostic tools in the ability to diagnose acute rejection

Inactive Publication Date: 2017-02-02
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current monitoring and diagnostic tools are limited in their ability to diagnose acute rejection at early stages e.g. acute kidney allograft rejection is currently diagnosed following needle core biopsy of the graft, a highly invasive procedure precipitated by crude biomarkers such as an increase in the levels of creatinine in a recipients serum (Girlanda et al., 2007, Semin Nephrol.
Allograft biopsies are currently highly invasive and are plagued by a number of complications including bleeding of the site of puncture, shock, allograft fistulas, and even graft loss and the biopsy procedure carries a greater risk in children.
However, despite this success, transplant recipients still exhibit much higher morbidity and mortality than the general population.
Immunosuppression related toxicities can be significant.

Method used

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  • Use of micro-ribonucleic acid (MIRNA) to diagnose transplant rejection and tolerance of immunosuppression therapy
  • Use of micro-ribonucleic acid (MIRNA) to diagnose transplant rejection and tolerance of immunosuppression therapy
  • Use of micro-ribonucleic acid (MIRNA) to diagnose transplant rejection and tolerance of immunosuppression therapy

Examples

Experimental program
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Effect test

example 1

Identification of Serum miRNA Signatures for the Detection and Prediction of Acute Cellular Rejection (ACR)

[0149]The results presented herein demonstrate that the miRNA profiles obtained at the time of clinically indicated biopsy are diagnostic of biopsy-confirmed acute rejection at any time after transplantation.

[0150]miRNA profiling was performed on 233 serum samples from 42 clinical trial participants from the National Institutes of Health Immune Tolerance in Transplantation-30 (ITN-30) study. This included 33 subjects randomized to immunosuppression withdrawal and 9 subjects randomized to maintenance, using the miRCURY LNA™ Universal RT microRNA PCR v3 panel (Exiqon, Denmark). The primary aims of this study were: 1) to identify serum miRNA signatures for diagnosis of acute cellular rejection (ACR) events; 2) to identify serum miRNA signatures for prediction of ACR events; 3) to identify serum miRNA signatures to differentiate subjects who fail immunosuppression withdrawal from s...

example 2

Identification of Serum miRNA Signatures for the Prediction of Immunosuppression Minimization Tolerance

[0153]These experiments were designed to identify additional clinically relevant biomarkers for immunosuppression minimization that are predictive of which subjects will be able to tolerate lower doses of medication without inducing rejection. To identify each tolerance biomarkers, 10 serum samples from those subjects who were tolerant at the 25% immunosuppression dose (also meant by that a decrease of the initial IST dose by 75%) were compared with 11 serum samples from subjects who failed at the 25% IST dose (these serum samples were taken 58 days on average before rejection occurred). The 25% IST dose was used as the basis for this comparison because a large proportion of subjects (40% of all participants) failed at this stage, and this may represent where major changes occur in serum miRNAs that best differentiate patients who may tolerate or fail at lower IST doses As shown in...

example 3

Replication of miRNA Sera Signatures for Detection and Prediction of Acute Cellular Rejection (ACR)

[0156]To initially replicate the list of 23 ACR-associated miRNAs as well as the 3-miRNA signature identified previously for ACR diagnosis signature (Phase I study, presented previously in Example 1), miRNA profiling of serum samples from two independent studies were subsequently analyzed via the 752 miRCURY LNA™ Universal RT microRNA PCR v3 panels from Exiqon (Denmark). The first study comprised 15 ACR and 5 non-ACR serum samples from the ITN participants who were not randomized to IST withdrawal or maintenance. The second study comprised 4 ACR and 11 non-ACR samples from the NIH-CTOT03 prospective study. After excluding miRNAs that failed standard quality control (QC) measures, 20 of the 23 ACR-associated miRNAs were included in logistic regression modeling to test their association with ACR. As shown in Table 3, all 20 miRNAs were replicated in this follow-up study.

[0157]The perform...

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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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of U.S. Provisional Application No. 61 / 977,980, filed Apr. 10, 2014, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under grants 5U01A1063589-0551 and 5U01A1063589-05 and ITN00111-00sc used for the Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (AWISH) with a ClinicalTrials.gov Identifier: NCT00135694 awarded by National Institute of Allergy and Infectious Diseases (NIAID). The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Solid organ transplantation provides life-saving therapy for patients with end-stage organ disease. In 2010, a total of 28,664 transplants were performed in the U.S., including 16,899 kidney, 6291 liver, 2333 heart, and 1770 lung transplants (Engels et al., 2011,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G06F19/00A61B5/15A61B10/00G06F19/20G16B25/10G16B25/20
CPCG06F19/3437G06F19/20A61B2010/0061A61B10/0038A61B10/007A61B5/15C12Q1/6883G16H50/50G16B25/00C12Q2600/178A61B5/150015G16B25/20G16B25/10C12Q2600/158C12N15/113
Inventor SHAKED, ABRAHAMCHANG, BAO-LIKEATING, BRENDANGUETTOUCHE, TOUMY
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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