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NZ769129B2 - Method and kits for prediction of acute rejection and renal allograft loss using pre-transplant transcriptomic signatures in recipient blood - Google Patents

Method and kits for prediction of acute rejection and renal allograft loss using pre-transplant transcriptomic signatures in recipient blood

Info

Publication number
NZ769129B2
NZ769129B2 NZ769129A NZ76912919A NZ769129B2 NZ 769129 B2 NZ769129 B2 NZ 769129B2 NZ 769129 A NZ769129 A NZ 769129A NZ 76912919 A NZ76912919 A NZ 76912919A NZ 769129 B2 NZ769129 B2 NZ 769129B2
Authority
NZ
New Zealand
Prior art keywords
gene
genes
expression
value
signature set
Prior art date
Application number
NZ769129A
Other versions
NZ769129A (en
Inventor
Barbara Murphy
Weijia Zhang
Original Assignee
Icahn School Of Medicine At Mount Sinai
Filing date
Publication date
Application filed by Icahn School Of Medicine At Mount Sinai filed Critical Icahn School Of Medicine At Mount Sinai
Priority claimed from PCT/US2019/027618 external-priority patent/WO2019204267A1/en
Publication of NZ769129A publication Critical patent/NZ769129A/en
Publication of NZ769129B2 publication Critical patent/NZ769129B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Abstract

Disclosed herein are gene signature sets expressed by kidney allograft recipients prior to transplant that determine the risk for acute rejection (AR) post-transplant and methods of using the gene signature sets for identifying renal allograft recipients at risk for acute rejection. Also disclosed herein are kits for use in the invention which comprise primer pairs for the gene signature sets.

Claims (17)

WHAT IS CLAIMED IS:
1. A method for identifying a renal allograft recipient at risk of developing acute rejection after transplantation comprising the steps of (a) determining the expression levels of a gene signature set in a pre-transplant blood specimen from the renal allograft recipient, wherein the gene signature set comprises at least the genes GZMH, ADGRG1, S1PR5, FGFBP2, NKG7, PRF1, KIAA1671, LAG3, TARP, FCRL6, FASLG, TBX21, TOX, , CD8A, 1, CCR5, LDOC1L, CCDC102A, HOPX, PRKCH, SLC25A34, and F12; (b) comparing the expression levels of the gene signature set with the sion levels of a gene ure set in a l, and (c) determining the recipient will be at risk for allograft rejection if the expression level of one or more genes in the gene ure set in the specimen is altered from the expression level of the same one or more genes in the gene signature set in the control.
2. The method of claim 1 wherein the alteration comprises an increase or a decrease in the expression level of one or more genes in the gene signature set in the specimen compared to the same one or more genes in the gene signature set in the control.
3. The method of claims 1 or 2 wherein the alteration comprises an increase and a decrease in the expression level of one or more genes in the gene signature set in the specimen compared to the same one or more genes in the gene ure set in the control.
4. The method of any one of claims 1-3,wherein the determining step comprises applying the expression levels determined in the patient’s sample to a ed cumulative risk score r = -(log10(p1)*g1+ log10(p2)*g2+… (pi)*gi+... + log10(p23)*g23), where pi is the significance p value of t-test on expression values for gene i ( i=1…23) between the EAR vs the non-EAR groups in the training set, gi is a logic number for gene i ( i=1…23), 1 (if the expression value of gene i is greater than the median expression value of the EAR group of the training set for an upregulated gene or if the expression value of gene i is less than the median expression value of the 1005914902 EAR group of the training set for a downregulated gene), or -1 (if the expression value of gene i is less than the median value of the non-EAR group of the training set for an upregulated gene or if the expression value of gene i is greater than the median value of the non-EAR group of the training set for a downregulated gene), or 0 (if the sion value of gene i is between the median values of the EAR and the non-EAR groups of the training set) that can be used as a risk score for acute rejection for each patient.
5. The method of any one of claims 1-4 n the expression levels are determined by a method selected from the group ting of Nanostring, TREx and quantitative polymerase chain reaction (qPCR).
6. A method for identifying a renal allograft recipient at risk of acute rejection of the allograft before transplantation comprising the steps of (a) ing mRNA from a blood specimen obtained from a renal allograft recipient;(b) synthesizing cDNA from the mRNA; (c) determining the expression levels of a gene signature set in said recipient’s blood, wherein the gene signature set comprises at least the genes GZMH, ADGRG1, S1PR5, , NKG7, PRF1, 71, LAG3, TARP, FCRL6, FASLG, TBX21, TOX, ZNF831, CD8A, C1orf21, CCR5, LDOC1L, CCDC102A, HOPX, PRKCH, SLC25A34, and F12; (d) identifying the allograft recipient as being at risk for acute rejection and allograft loss if the expression level of one or more genes in the gene signature set in the allograft recipient’s blood specimen is altered compared to the expression level of the same one or more genes in a control blood specimen, and wherein the recipient fied as being at risk for acute rejection or allograft loss is to be treated with induction therapy.
7. The method of claim 6 wherein said induction therapy comprises a therapeutically effective amount of anti-thymocyte globulin or Campath-1H.
8. The method of any one of claims 6-7, wherein the expression levels are ined by a method selected from the group consisting of Nanostring, TREx, and quantitative polymerase chain reaction (qPCR). 1005914902
9. A kit for identifying renal aft recipients at risk for acute rejection and allograft loss comprising: primer pairs for a gene signature set, s, positive and negative controls and instructions for use, wherein the gene signature set comprises at least the genes GZMH, ADGRG1, S1PR5, FGFBP2, NKG7, PRF1, KIAA1671, LAG3, TARP, FCRL6, FASLG, TBX21, TOX, ZNF831, CD8A, C1orf21, CCR5, LDOC1L, CCDC102A, HOPX, PRKCH, SLC25A34, and F12.
10. The kit of claim 9 further comprising a eeping gene panel and primers for the housekeeping gene panel.
11. The kit of claim 10 wherein the genes in said housekeeping gene panel is selected from the group consisting of CHTOP, YKT6, RER1, PI4KB, ZDHHC5, TMEM248, C6orf89, SMU1, SHC1, DLST, UBE2Q1, FBXO18 and SLC35E1.
12. The method of claims 6 or 7 further comprising calculating a weighted cumulative score (r = -(log10(p1)*g1+ log10(p2)*g2+… +log10(pi)*gi+... + log10(p23)*g23), where pi is the significance p value of t-test on expression values for gene i ( i=1…23) between the EAR vs the non-EAR groups in the training set, gi is a logic number for gene i ( i=1…23), 1 (if the expression value of gene i is greater than the median expression value of the EAR group of the training set for an upregulated gene or if the expression value of gene i is less than the median expression value of the EAR group of the training set for a gulated gene), or -1 (if the expression value of gene i is less than the median value of the non-EAR group of the training set for an upregulated gene or if the expression value of gene i is greater than the median value of the non- EAR group of the training set for a downregulated gene), or 0 (if the sion value of gene i is between the median values of the EAR and the non-EAR groups of the ng set) that can be used as a risk score for acute rejection for each patient.
13. The method of claim 12 wherein the probability score is determined using a computer based system.
14. The method of any one of claims 12 or 13 wherein the probability score is used to determine the cutoff value. 1005914902
15. A method for ing a renal allograft patient for induction therapy prior to transplantation to reduce the risk of renal acute rejection or allograft loss which comprises (a) determining the sion levels of a gene signature set in a pre-transplant blood specimen from the renal allograft recipient, wherein the gene signature set comprises at least the genes GZMH, ADGRG1, S1PR5, FGFBP2, NKG7, PRF1, KIAA1671, LAG3, TARP, FCRL6, FASLG, TBX21, TOX, ZNF831, CD8A, C1orf21, CCR5, LDOC1L, CCDC102A, HOPX, PRKCH, SLC25A34, and F12; (b) ing the expression level of a gene ure set obtained from the patient with the expression level of a gene signature set in a control sample obtained from an allograft recipient that did not suffer acute ion; and (c) selecting the patient for treatment with ion therapy if the expression level of one or more genes in the gene signature set from the patient is altered compared to the sion level of one or more of the genes in the gene signature set in the control, wherein induction therapy is to be stered to said selected patient.
16. The method of claim 15 wherein said induction therapy comprises a therapeutically effective amount of anti-thymocyte globulin or Campath-1H.
17. Use of a therapeutically effective amount of hymocyte globulin or Campath-1H in the preparation of a medicament for reducing the risk of renal acute rejection or allograft loss in a renal allograft patient selected by: (a) determining the expression levels of a gene signature set in a pre-transplant blood specimen from the renal allograft recipient, wherein the gene signature set comprises at least the genes GZMH, ADGRG1, S1PR5, FGFBP2, NKG7, PRF1, KIAA1671, LAG3, TARP, FCRL6, FASLG, TBX21, TOX, ZNF831, CD8A, C1orf21, CCR5, LDOC1L, CCDC102A, HOPX, PRKCH, SLC25A34, and F12; (b) comparing the sion level of a gene signature set obtained from the patient with the expression level of a gene signature set in a l sample obtained from an allograft recipient that did not suffer acute rejection; wherein the medicament is to be administered to the t if the expression level of one or more genes in the gene signature set from the patient is altered compared 1005914902 to the sion level of one or more of the genes in the gene signature set in the control.
NZ769129A 2019-04-16 Method and kits for prediction of acute rejection and renal allograft loss using pre-transplant transcriptomic signatures in recipient blood NZ769129B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862658066P 2018-04-16 2018-04-16
PCT/US2019/027618 WO2019204267A1 (en) 2018-04-16 2019-04-16 Method and kits for prediction of acute rejection and renal allograft loss using pre-transplant transcriptomic signatures in recipient blood

Publications (2)

Publication Number Publication Date
NZ769129A NZ769129A (en) 2025-05-30
NZ769129B2 true NZ769129B2 (en) 2025-09-02

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