PREDICTIVE BIOMARKERS FOR CHRONIC ALLOGRAFT NEPHROPATHY

• US 20100022627A1
• Filed: 04/02/2007
• Published: 01/28/2010
• Est. Priority Date: 04/03/2006
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Scherer, Andreas
• Application Number:
  US12/295,298
• Publication Number:
  US 20100022627A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/245 Transplantation related diseases, e.g. graft versus host disease
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 2800/60 Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The invention relates to the analysis and identification of genes that are modulated in transplant rejection. This alteration of gene expression provides a molecular signature to accurately detect transplant rejection.

Claims

1. A method for predicting the onset of a rejection of a transplanted organ in a subject, comprising the steps of:

(a) obtaining a post-transplantation sample from the subject;

(b) determining the magnitude of gene expression in the post-transplantation sample of a combination of a plurality of genes selected from the group consisting of the genes set forth in Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model;

(c) comparing the magnitude of gene expression of the combination of the plurality of genes in the post-transplantation sample with the magnitude of gene expression of the same combination of the plurality of genes in a control sample; and

(d) determining whether the magnitude of gene expression of the combination of the plurality of genes is up-regulated or down-regulated relative to the control sample, wherein up-regulation or down-regulation of the magnitude of expression of the combination of the plurality of genes indicates that the subject is likely to experience transplant rejection, thereby predicting the onset of rejection of the transplanted organ in the subject.

2. The method of claim 1, wherein the post-translation sample comprises cells obtained from the subject.

3. The method of claim 1, wherein the post-translation sample is selected from the group consisting of:

a graft biopsy;

blood;

serum; and

urine.

4. The method of claim 1, wherein the rejection is chronic/sclerosing allograph nephropathy.

5. The method of claim 1, wherein the magnitude of expression in the post-transplantation sample differs from the magnitude of expression in the control sample by a factor of at least about 1.5.

6. The method of claim 1, wherein the magnitude of expression in the post-transplantation sample differs from the magnitude of expression in the control sample by a factor of at least about 2.

16. The method according to claim 1, wherein the transplanted subject is a kidney transplanted subject.

17. The method according to of claim 1, wherein the magnitude of gene expression is assessed by detecting the presence of a protein encoded by the combination of the plurality of genes.

18. The method of claim 17, wherein the presence of the protein is detected using a reagent which specifically binds to the protein.

7. A method for predicting the onset of a rejection of a transplanted organ in a subject, comprising the steps of:

(a) obtaining a post-transplantation sample from the subject;

(b) determining the gene expression pattern in the post-transplantation sample of a combination of a plurality of genes selected from the group consisting of the genes set forth in Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model; and

(c) comparing the gene expression pattern of the combination of the plurality of genes in the post-transplantation sample with the gene expression pattern of the same combination of the plurality of genes in a control sample, wherein a similarity in the gene expression pattern of the combination of the plurality of genes in the post-transplantation sample compared to the gene expression pattern of the same combination of the plurality of genes in a control sample gene expression pattern indicates indicates that the subject is likely to experience transplant rejection, thereby predicting the onset of rejection of the transplanted organ in the subject.

8. The method of claim 7, wherein the post-transplantation sample comprises cells obtained from the subject.

9. The method of claim 7, wherein the post-transplantation sample is selected from the group consisting of:

a graft biopsy;

blood;

serum; and

urine.

10. The method of claim 7, wherein the rejection is chronic/sclerosing allograft nephropathy.

11. A method of monitoring transplant rejection in a subject, comprising the steps of:

(a) taking as a first baseline value the magnitude of gene expression of a combination of a plurality of genes in a sample obtained from a transplanted subject who is known not to develop rejection;

(b) taking as a second value the magnitude of gene expression of the same combination of a the plurality of genes in a sample obtained from a the transplanted subject post-transplantation; and

(c) comparing the first baseline value with the second value, wherein a first baseline value lower or higher than the second value predicts that the transplanted subject is at risk of developing rejection, wherein the combination of the plurality of genes are selected from the group consisting of the genes set forth in Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model, thereby monitoring transplant rejection in the subject.

12. A method of monitoring transplant rejection in a subject, comprising the steps of:

(a) taking as a first value a pattern of gene expression corresponding to a combination of a plurality of genes from a sample obtained from a donor subject at the day of transplantation;

(b) taking as a second value a pattern of gene expression corresponding to the combination of the plurality of genes from a sample obtained from a recipient subject post-transplantation; and

(c) comparing the first value with the second value, wherein a first value lower or higher than the second value predicts that the recipient subject is at risk of developing rejection;

wherein the a combination of the plurality of genes selected from the group consisting of the genes set forth in Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model, thereby monitoring transplant rejection in the subject.

19. The method of claim 12, wherein the pattern of gene expression is detected by techniques selected from the group consisting of Northern blot analysis, reverse transcription PCR and real time quantitative PCR.

13. A method for monitoring modifying transplant rejection treatment in a subject at risk thereof, comprising the steps of:

(a) obtaining a pre-administration sample or samples from a transplanted subject prior to administration of a rejection inhibiting agent;

(b) detecting the pattern of gene expression of a plurality of genes in the pre-administration sample or samples; and

(c) obtaining a post-administration sample or samples from the transplanted subject;

(d) detecting the pattern of gene expression of a the plurality of genes in the post-administration sample or samples;

(e) comparing the pattern of gene expression of the plurality of genes in the pre-administration sample with the pattern of gene expression in the post-administration sample or samples; and

(f) adjusting the agent accordingly, wherein the plurality of genes are selected from the group consisting of the genes Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model, thereby modifying transplant refection treatment.

14. A method for preventing, inhibiting, reducing or treating transplant rejection in a subject in need of such treatment comprising administering to the subject a compound that modulates the synthesis, expression or activity of one or more genes or gene products encoded thereby, said genes being selected from the group consisting of the genes set forth in Table 4, Table 5, Table 6, Table 7, and Table 8 in combination with a predictive model selected from the group consisting of a PLDSA model and an OPLS model, such that at least one symptom of rejection is ameliorated.

15. (canceled)

20-24. -24. (canceled)