US-12618111-B2 - Methods of diagnosing inflammatory bowel disease through RNASET2

Abstract

The present invention describes methods of diagnosing inflammatory bowel disease, including but not limited to Crohn's Disease (CD), Ulcerative Colitis (UC), and/or Medically Refractive Ulcerative Colitis (MR-UC), using RNASET2, TL1A and/or IFN-γ. The invention further provides a process for patient identification and/or stratification.

Inventors

• Rebecca Gonsky
• Stephan R. Targan
• Richard L. DEEM
• Philip Fleshner
• Dermot P. McGovern
• Janine Bilsborough

Assignees

• CEDARS-SINAI MEDICAL CENTER

Dates

Publication Date

20260505

Application Date

20211028

Claims (20)

1. 1 . A method of treating inflammatory bowel disease (IBD) in a subject, the method comprising administering a therapeutically effective amount of an anti-Tumor Necrosis Factor Ligand 1 (anti-TL1A) antibody to the subject, wherein the subject has been identified as having one or more RNase T2 (RNASET2) gene alleles selected from the group consisting of an “A” allele of rs1819333, a “T” allele of rs2149092, a “G” allele of rs9355610, a “T” allele of rs2149085, a “G” allele of rs1410295, and a “G” allele of rs9366093, and wherein methylation of the RNASET2 gene of the subject is increased as compared to a control subject who has not been diagnosed with IBD.
2. 2 . The method of claim 1 , wherein the inflammatory bowel disease (IBD) is Crohn's disease (CD).
3. 3 . The method of claim 1 , wherein the subject is refractory to one or both of thiopurine and anti-Tumor Necrosis Factor (anti-TNF) therapy.
4. 4 . The method of claim 1 , wherein the subject is determined to need surgical intervention for disease management or wherein the subject has undergone surgical intervention for disease management.
5. 5 . The method of claim 4 , wherein the surgical intervention is intestinal resection.
6. 6 . A method of identifying a subject having inflammatory bowel disease (IBD) who is likely to benefit from treatment with an anti-Tumor Necrosis Factor Ligand 1 (anti-TL1A) antibody, wherein the method comprises: a) assessing a biological sample from the subject to determine the presence or absence of one or more RNase T2 (RNASET2) gene alleles selected from the group consisting of an “A” allele of rs1819333, a “T” allele of rs2149092, a “G” allele of rs9355610, a “T” allele of rs2149085, a “G” allele of rs1410295, and a “G” allele of rs9366093; and b) assessing the biological sample from the subject to determine a level of methylation of RNASET2; wherein the presence of one or more of the alleles and/or increased methylation of RNASET2 indicates that the subject is likely to benefit from treatment with the anti-TL1A antibody.
7. 7 . The method of claim 6 , wherein the inflammatory bowel disease (IBD) is Crohn's disease (CD).
8. 8 . The method of claim 6 , wherein the subject is refractory to one or both of thiopurine and anti-Tumor Necrosis Factor (anti-TNF) therapy.
9. 9 . The method of claim 6 , wherein the subject is determined to need surgical intervention for disease management or wherein the subject had surgical intervention for disease management.
10. 10 . The method of claim 9 , wherein the surgical intervention is intestinal resection.
11. 11 . A method of treating inflammatory bowel disease (IBD) in a subject, the method comprising administering a therapeutically effective amount of an anti-Tumor Necrosis Factor Ligand 1 (anti-TL1A) antibody to the subject, wherein the subject has been identified as having each of an “A” RNase T2 (RNASET2) gene allele of rs1819333, a “G” RNASET2 allele of rs9355610, and a “T” RNASET2 allele of rs2149085.
12. 12 . The method of claim 1 , wherein the inflammatory bowel disease (IBD) is ulcerative colitis (UC) or medically refractive ulcerative colitis (mrUC).
13. 13 . The method of claim 6 , wherein the inflammatory bowel disease (IBD) is ulcerative colitis (UC) or medically refractive ulcerative colitis (mrUC).
14. 14 . The method of claim 1 , wherein the anti-TL1A antibody comprises a neutralizing TL1A antibody.
15. 15 . The method of claim 6 , wherein the anti-TL1A antibody comprises a neutralizing TL1A antibody.
16. 16 . The method of claim 1 , wherein the subject is anti-neutrophil cytoplasmic antibody (ANCA) seropositive.
17. 17 . The method of claim 1 , wherein the subject is identified as having the one or more RNASET2 gene alleles by analysis of samples isolated from the peripheral T cells and/or small bowel surgical resections of the subject.
18. 18 . The method of claim 6 , wherein the subject is identified as having the one or more RNASET2 gene alleles by analysis of samples isolated from the peripheral T cells and/or small bowel surgical resections of the subject.
19. 19 . The method of claim 1 , wherein the subject has been identified as having one or more of the “T” allele of rs2149085, the “T” allele of rs2149092, and the “A” allele of rs1819333.
20. 20 . The method of claim 6 , wherein the subject has been identified as having one or more of the “T” allele of rs2149085, the “T” allele of rs2149092, and the “A” allele of rs1819333.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 16/084,858, filed Sep. 13, 2018, now U.S. Pat. No. 11,186,872, issued Nov. 30, 2021, which is a U.S. National Phase Application under 35 U.S.C. § 371 of International Patent Application No. PCT/US2017/023082, filed Mar. 17, 2017, which claims the benefit of U.S. Provisional Patent Application No. 62/457,048, filed Feb. 9, 2017, and U.S. Provisional Patent Application No. 62/309,817, filed Mar. 17, 2016, the disclosure of each of which is incorporated by reference herein in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant Nos. DK043211, DK046763, DK062413, HS021747, AI067068, DE023798, DK084554, RR033176 and TR000124 awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING This application incorporates by reference in its entirety the Computer Readable Form (CRF) of a Sequence Listing in ASCII text format submitted via Patent Center. The Sequence Listing text file submitted via Patent Center is entitled “14463-528-999_SEQ LISTING.txt”, was created on Nov. 5, 2025, and is 13,170 bytes in size. FIELD OF INVENTION The invention relates to inflammatory bowel disease and RNASET2 as a biomarker for disease severity and targeting anti-TL1A therapy. BACKGROUND All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. Inflammatory bowel disease (IBD) has two common forms, Crohn's disease (CD) and ulcerative colitis (UC), which are chronic, relapsing inflammatory disorders of the gastrointestinal tract. Genetic factors play an important role in IBD pathogenesis, as evidenced by the increased rates of IBD in Ashkenazi Jews, familial aggregation of IBD, and increased concordance for IBD in monozygotic compared to dizygotic twin pairs (S. Vermeire, P. Rutgeerts, Genes Immun 6, 637 (2005)). Moreover, genetic analyses have linked IBD to specific genetic variants. CD and UC are thought to be related disorders that share some genetic susceptibility loci but differ at others. IBD is generally believed to be triggered in genetically susceptible individuals by an inappropriate immune response to the commensal flora. The high clinical heterogeneity and genetic complexity of CD and UC suggest that the underlying biological pathways driving disease almost certainly differ in subgroups of patients. Thus, the development of early and targeted therapeutics requires subgroup stratification and prognostic biomarker identification, particularly in predicting an overall mild, compared to severe, disease course. Although 201 IBD susceptibility loci have been identified, little is known regarding their functional significance. Genetic variation in TNFSF15 is associated with CD in multiple populations, and the protein it encodes, TL1A, is a key mediator of mucosal inflammation. TL1A expression is up-regulated in inflamed regions of the intestine in both CD and UC. In IBD patients, elevated TL1A levels correlate with TNFSF15 genotype and disease severity. CD patients with elevated serum/tissue levels of TL1A have increased risk of developing fibrosis/stricturing disease behavior. In vitro, TL1A synergizes with interleukin 12 (IL-12) and interleukin 18 (IL-18) (12/18), leading to rapid enhancement of IFN-γ production, another key mediator of mucosal inflammation. Therefore, there remains a need in the art for methods of diagnosing and identifying patients for treatment with IBD, CD, UC and/or MR-UC. BRIEF DESCRIPTION OF THE FIGURES Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive. FIG. 1 depicts RNASET2 eQTL microarray in uninvolved small intestine, in accordance with various embodiments of the invention. FIG. 2 shows that the RNASET2 major allele is associated with decreased expression of RNASET2 in sigmoid colon and rectum of CD patients, in accordance with various embodiments of the invention. FIG. 3 shows that the RNASET2 major allele is associated with decreased expression of RNASET2 in sigmoid colon and rectum of UC patients, in accordance with various embodiments of the invention. FIG. 4 shows that the RNASET2 risk allele is associated with decreased expression of RNASET2 in inflamed large bowel in CD and UC patients, in accordance with various embodiments of the invention. Similar results were observ