Methods for predicting acute rejection in heart recipients

Patent metadata

Field	Value
Publication number	US-2017130267-A1
Application number	US-201515125355-A
Country	US
Kind code	A1
Filing date	Mar 17, 2015
Priority date	Mar 17, 2014
Publication date	May 11, 2017
Grant date	—

Abstract

The present invention relates to method for predicting acute rejection in heart recipients. In particular, the present invention relates to a method for predicting acute rejection in a heart recipient comprising the steps consisting of i) determining the expression level (ELi) of at least one miRNAi selected from the group consisting of miR-155, miR-10 a , miR-92 a and miR-31 in a blood sample obtained from the heart recipient, ii) comparing the expression level (ELi) determined at step i) with a predetermined reference level (ELRi) and iii) and concluding that the recipient has a high risk of developing acute rejection when the level the expression level (ELi) determined at step i) is different (higher or lower) than the predetermined reference level (ELRi).

First claim

1 . A method for predicting acute rejection in a heart transplant recipient comprising the steps of i) determining an expression level (ELi) of at least one miRNAi selected from the group consisting of miR-155, miR-10a, miR-92a and miR-31 in a blood sample obtained from the heart transplant recipient, ii) comparing the expression level (ELi) determined at step i) with a predetermined reference level (ELRi) and iii) and concluding that the heart transplant recipient has a high risk of developing acute rejection when the expression level (ELi) determined at step i) is different than the predetermined reference level (ELRi).

2 . The method of claim 1 wherein the at least one miRNAi is miR-155 and wherein the heart transplant recipient has a high risk of having acute rejection when an expression level for miR-155 (EL miR155 ) determined at step i) is higher than a predetermined reference level for miR-155 (ELR miR155 ).

3 . The method of claim 1 wherein the at least one miRNAi is miR-10a and wherein the heart transplant recipient has a high risk of having acute rejection when an expression level for miR-10a (EL miR10a ) determined at step i) is lower than a predetermined reference level for miR 10 a (ELR miR10a ).

4 . The method of claim 1 wherein the at least one miRNAi is miR-92a and wherein the heart transplant recipient has a high risk of having acute rejection when an expression level for miR-92a (EL miR92a ) determined at step i) is higher than a predetermined reference level for miR-92a (ELR miR92a ).

5 . The method of claim 1 wherein the at least one miRNAi is miR-31 and wherein the heart transplant recipient has a high risk of having acute rejection when an expression level for miR-31 (EL miR31 ) determined at step i) is higher than a predetermined reference level for miR-31 (ELR miR31 ).

6 . The method of claim 1 wherein the at least one miRNAi includes miR-155 and miR-10a and wherein the heart transplant recipient has a high risk of having acute mediated antibody rejection (AMR) when an expression level for miR-155 (EL miR55 ) determined at step i) is higher than a predetermined reference level for miR-155 (ELR miR155 ) and an expression level for miR-10a (EL miR10a ) determined at step i) is lower than the predetermined reference level for miR-10a (ELR miR10a ).

7 . The method of claim 1 wherein the at least one miRNAi includes miR-155 and miR-10a and wherein the heart transplant recipient has a high risk of having acute cellular rejection (ACR) when the expression level for miR-155 (EL miR155 ) determined at step i) is higher than a predetermined reference level for miR-155 (ELR miR55 ) and an expression level for miR-10a (EL miR10a ) determined at step i) is higher than a predetermined reference level for miR-10a (ELR miR10a ).

8 . A method for determining whether a heart transplant recipient is eligible for treatment of acute rejection comprising
i) predicting acute rejection by
a) determining an expression level (ELi) of at least one miRNAi selected from the group consisting of miR-155, miR-10a, miR-92a and miR-31 in a blood sample obtained from the heart transplant recipient, b) comparing the expression level (ELi) determined at step i) with a predetermined reference level (ELRi) and c) concluding that the heart transplant recipient has a high risk of developing acute rejection when at least one expression level (ELi) determined at step a) is different than the predetermined reference level (ELRi); and
ii) determining that the heart transplant recipient is eligible for said treatment when it is concluded that the heart transplant recipient has a high risk of developing acute rejection.

9 . The method of claim 8 wherein the treatment comprises administering a short course of high-dose corticosteroids.

10 . The method of claim 8 wherein the treatment comprises administering at least one antibody selected from the group consisting of anti-CD40 antibodies, anti-CD20 monoclonal antibodies, anti-CD22 antibodies, anti-CD27 antibodies, anti-CD 19 antibodies anti-APRIL antibodies and anti-IL-6 antibodies.

11 . The method of claim 8 wherein the treatment requires includes blood exchanges to remove antibodies targeting the graft which are present in a circulating compartment of the heart transplant recipient.

12 . The method of claim 9 , wherein the corticosteroids include Prednisolone and/or Hydrocortisone.

13 . A method for treating acute rejection in a heart transplant recipient comprising
i) predicting acute rejection by
a) determining an expression level (ELi) of at least one miRNAi selected from the group consisting of miR-155, miR-10a, miR-92a and miR-31 in a blood sample obtained from the heart transplant recipient,
b) comparing the expression level (ELi) determined at step i) with a predetermined reference level (ELRi) and
c) concluding that the heart transplant recipient has a high risk of developing acute rejection when at least one expression level (ELi) determined at step a) is different than the predetermined reference level (ELRi); and, when it is concluded that the heart transplant recipient has a high risk of developing acute rejection,
ii) treating the heart transplant recipient for acute rejection.

14 . The method of claim 13 wherein the step of treating comprises one or more of:
administering a short course of high-dose corticosteroids;
administering at least one antibody selected from the group consisting of anti-CD40 antibodies, anti-CD20 monoclonal antibodies, anti-CD22 antibodies, anti-CD27 antibodies, anti-CD19 antibodies anti-APRIL antibodies and anti-IL-6 antibodies; and
blood exchanges to remove antibodies targeting the graft which are present in a circulating compartment of the heart transplant recipient.

15 . A method for determining an expression level (ELi) of at least one miRNAi selected from the group consisting of miR-155, miR-10a, miR-92a and miR-31 in a blood sample obtained from a heart transplant recipient, comprising
measuring a level of the at least one miRNA using: an amplification-based method, a hybridization-based method, a sequencing-based method, a ribonuclease protection assay (RPA) or mass spectroscopy.

16 . The method of claim 15 , wherein the amplification-based method is quantitative polymerase chain reaction (qPCR).

17 . An analysis method, comprising the steps of:
obtaining a blood sample from a subject identified as being a potential heart transplant recipient or that has received a heart transplant; and determining an expression level (Eli) of at least one miRNAi selected from the group consisting of miR-155, miR-10a, miR-92a, and miR-31 in the blood sample.

Assignees

• Inserm (Institut Nat De La Santé Et De La Rech Médicale)
• Univ Paris Diderot Paris 7
• Université Paris Descartes
• Assist Publique-Hôpitaux De Paris (Aphp)
• Inserm (Institut Nat De La Sante Et De La Recerrche Medicale)
• Univ Paris Diderot - Paris 7
• Univ Paris Descartes
• Assist Publique-Hopitaux De Paris (Aphp)

Inventors

• Duong Van Huyen Jean-Paul
• Jouven Xavier
• Loupy Alexandre
• Tible Marion

Classifications

• C12Q2600/178

  miRNA, siRNA or ncRNA · CPC title

• C12Q1/6883 Primary

  for diseases caused by alterations of genetic material · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• C12Q2600/158

  Expression markers · CPC title