Biomarkers for inflammatory bowel disease

Patent metadata

Field	Value
Publication number	US-11041206-B2
Application number	US-201715642252-A
Country	US
Kind code	B2
Filing date	Jul 5, 2017
Priority date	Jul 5, 2016
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention provides a method of assessing whether an individual is at high risk or low risk of inflammatory bowel disease (IBD) progression by determining the expression level of two or more genes in a whole blood sample. Also provided are methods for treating IBD in an individual who is determined to be at high risk or low risk for IBD progression, and kits for assessing whether an individual is at high risk or low risk for IBD progression. Arrays, and methods of providing arrays, of patient-identified selected gene expression products from a whole blood sample of a patient are also provided.

First claim

The invention claimed is:

1. A method of treating an individual who presents with one or more symptoms of inflammatory bowel disease (IBD), the method comprising:
(a) identifying said individual as at high risk or at low risk of IBD progression by determining the expression level of three or more genes in a whole blood sample obtained from the individual, wherein the three or more genes are selected from the group consisting of:
arrestin domain containing 4 (ARRDC4);
guanylate binding protein 5 (GBP5);
purinergic receptor P2Y G-protein coupled, 14 (P2RY14);
vault RNA 1-1 (VTRNA1-1);
interleukin 18 receptor accessory protein (IL18RAP);
haptoglobin (HP);
nudix (nucleoside diphosphate linked moiety X)-type motif 7 (NUDT7);
granzyme H (GZMH);
T cell receptor gamma constant 2 (TRGC2);
lectin, galactoside-binding-like (LGALSL);
Fc receptor-like 5 (FCRL5);
interferon-induced protein 44-like (IFI44L);
long intergenic non-protein coding RNA 1136 (LINC01136);
lymphocyte antigen 96 (LY96);
granzyme K (GZMK); and
T Cell Receptor Gamma Variable 3 (TRGV3);

wherein said expression level relative to a known expression level for risk of IBD progression identifies said individual as being at high risk or at low risk of IBD progression; and
(b) treating said individual identified as being at high risk of IBD progression with a drug that is suitable for aggressive treatment of IBD; or treating said individual identified as being at low risk of IBD progression with a drug that is suitable for step-up treatment of IBD.

2. The method of claim 1 , wherein said individual is characterized as at high risk of IBD progression by:
a higher level of expression in whole blood of said three or more genes of the genes: ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, and GZMK, relative to-a control; and
a lower level of expression in whole blood of said three or more genes of the genes: LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3, relative to a control.

3. The method of claim 1 , wherein said risk of progression of IBD in said individual is determined by: calculating a risk score for said patient by
a) weighting the measured expression levels of the selected genes;
b) applying a logistic regression model to the weighted expression levels to determine the risk score,
wherein a risk score of less than 0.5 is indicative of low risk of IBD progression and a risk score of greater than 0.5 is indicative of high risk of IBD progression and

c) creating a report summarizing the result of said determination.

4. The method according to claim 2 , wherein the expression level of said three or more genes is determined using any one of real time quantitative PCR (RT-qPCR), digital PCR, microarray analysis, whole transcriptome shotgun sequencing, or direct multiplexed gene expression analysis.

5. The method according to claim 4 , wherein the expression level of said three or more genes is determined using RT-qPCR.

6. The method according to claim 4 , wherein the method comprises:
(i) providing a whole blood sample obtained from the individual;
(ii) extracting RNA from the whole blood sample;
(iii) converting the RNA into cDNA; and
(iv) performing anyone of RT-qPCR, digital PCR, or whole transcriptome shotgun sequencing to determine the expression level of the three or more genes.

7. The method according to claim 1 , further comprising:
(c) selecting an individual identified as one who is at high risk or low risk of IBD progression in step (a) for treatment for IBD.

8. The method according to claim 1 , further comprising:
(c) subjecting an individual identified as one who is at high risk or low risk of IBD progression in step (a) to treatment for IBD.

9. A method for treating inflammatory bowel disease (IBD) in an individual who is classified as having an IBD1 or IBD2 phenotype, wherein said IBD1 phenotype carries a high risk for IBD progression and said IBD2 phenotype carries a low risk for IBD progression, the method comprising:
(i) identifying said IBD1 or IBD2 classification for said individual, wherein said identification relies on a determination of expression levels of three or more genes, wherein the three or more genes are selected from the group consisting of: ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, GZMK, LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3, in a whole blood sample obtained from the individual,
wherein a higher level of expression of genes ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, and GZMK, and a lower level of expression of genes LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3 relative to the level of expression of these genes in an individual who has a low risk (IBD2) phenotype, indicates that the individual has a high risk (IBD1) phenotype, and wherein a lower level of expression of genes ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, and GZMK, and a higher level of expression of genes LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3 relative to the level of expression of these genes in an individual who has a high risk (IBD1) phenotype, indicates that the individual has a low risk (IBD2) phenotype, and
(ii) treating the individual classified as having an IBD1 phenotype for IBD with a drug that is suitable for aggressive treatment of IBD or treating the individual classified as having an IBD2 phenotype for IBD with a drug that is suitable for step up treatment of IBD.

10. The method according to claim 9 , wherein said identification in step (i) relies on a determination of the expression level in whole blood of three or more genes by RT-qPCR, digital PCR, microarray analysis, whole transcriptome shotgun sequencing, or direct multiplexed gene expression analysis.

11. The method according to claim 1 , wherein the IBD is ulcerative colitis (UC) or Crohn's disease.

12. An in vitro method of identifying a drug for inducing a low risk (IBD2) phenotype in an IBD patient, the method comprising:
providing (i) a whole blood sample obtained from the IBD patient prior to treatment with a drug, and (ii) a whole blood sample obtained from the IBD patient following treatment with the drug, wherein the IBD patient has been determined to have a high risk (IBD1) phenotype by identifying said IBD1 or IBD2 classification for said patient,
wherein said identification relies determining the expression levels of three or more genes, wherein the three or more genes are selected from the group consisting of: ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, GZMK, LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3, in the whole blood sample (i) obtained from the patient
wherein a higher level of expression of genes ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, and GZMK, and a lower level of expression of genes LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3 relative to the level of expression of these genes in an individual who has a low risk (IBD2) phenotype, indicates that the individual has a high risk (IBD1) phenotype, and
wherein a lower level of expression of genes ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, and GZMK, and a higher level of expression of genes LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3 relative to the level of expression of these genes in an individual who has a high risk (IBD1) phenotype, indicates that the individual has a low risk (IBD2) phenotype; and

determining the expression level of the three or more genes selected from the group consisting of ARRDC4, GBP5, P2RY14, VTRNA1-1, IL18RAP, HP, NUDT7, GZMH, TRGC2, GZMK, LGALSL, FCRL5, IFI44L, LINC01136, LY96, and TRGV3 in sample (ii);
where

Assignees

• Cambridge Entpr Ltd

Inventors

• Lyons Paul A
• Smith Kenneth G C
• Mckinney Eoin F
• Biasci Daniele
• Lee James

Classifications

• G16B25/10

  Gene or protein expression profiling; Expression-ratio estimation or normalisation · CPC title

• G16B25/20

  Polymerase chain reaction [PCR]; Primer or probe design; Probe optimisation · CPC title

• C12Q1/6883 Primary

  for diseases caused by alterations of genetic material · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title

• C12Q2600/136

  Screening for pharmacological compounds · CPC title