Methods for screening, treating and diagnosing inflammatory bowel disease and compositions thereof

• US 20040176293A1
• Filed: 12/18/2003
• Published: 09/09/2004
• Est. Priority Date: 12/18/2002
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Dorner, Andrew J., Peterson, Ron L.
• Application Number:
  US10/740,218
• Publication Number:
  US 20040176293A1
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 14/5431 IL-11
• CPC Class Codes: C07K 14/70539 MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: G01N 2800/065 Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

Methods and compositions for the identification of novel targets for diagnosis, prognosis, therapeutic intervention and prevention of IBD. In particular, the present invention is directed to the identification of novel targets that are IBD differential markers. The present invention is further directed to methods of high-throughput screening for test compounds capable of modulating the activity of proteins encoded by the novel targets. Moreover, the present invention is also directed to methods that can be used to assess the efficacy of test compounds and therapies for the ability to inhibit IBD. Methods for determining the long-term prognosis in a subject are also provided.

Claims

1. A method of treating a subject suffering from IBD comprising administering RegIII protein or Ins2 protein to the subject.

2. A method of treating a subject suffering from IBD comprising administering to the subject a plurality of proteins selected from the group consisting of RegIII, Ins2, RegI, and TFF2, provided said plurality of proteins does not contain only RegI and TFF2.

3. The method of claim 2, wherein the plurality of proteins comprises a combination of proteins.

4. A method of treating a subject diagnosed with IBD, the method comprising administering to the subject an isolated nucleic acid molecule encoding RegIII or Ins2 operably linked to at least one expression control sequence, wherein the RegIII protein or the Ins2 protein is expressed in the subject.

5. A method of treating a subject diagnosed with IBD comprising administering to the subject a plurality of isolated nucleic acid molecules encoding proteins selected from the group consisting of RegIII, Ins2, RegI, and TFF2, operably linked to at least one expression control sequence, provided said plurality of isolated nucleic acid molecules encoding proteins does not contain only RegI and TFF2.

6. A method of identifying a compound capable of increasing the activity of a protein selected from the group consisting of RegIII and Ins2 comprising the steps of:

(a) contacting a sample containing the protein with one of a plurality of test compounds; and

(b) comparing the activity of the protein in the contacted sample with that in a sample containing the protein not contacted with the test compound,

wherein a substantial increase in the activity of the protein in the contacted sample identifies the compound as an activator of protein activity useful in treating IBD.

7. A method of treating a subject suffering from IBD comprising administering to the subject a compound identified by the method of claim 6.

8. A method of identifying a compound capable of increasing the activities of a plurality of proteins selected from the group consisting of RegIII, Ins2, RegI, and TFF2, provided said plurality of proteins does not contain only RegI and TFF2, comprising the steps of:

(a) contacting a sample containing the plurality of proteins with one of a plurality of test compounds; and

(b) comparing the activities of the plurality of proteins in the contacted sample with those in a sample containing the plurality of proteins not contacted with the test compound,

wherein increases in the activities of the plurality of proteins in the contacted sample identify the compound as an activator of protein activity useful in treating IBD.

9. A method of treating a subject suffering from IBD comprising administering to the subject a compound identified by the method of claim 8.

10. A method of treating a subject suffering from IBD comprising administering to the subject a compound that increases the activity of RegIII protein and/or the activity of Ins2 protein.

11. A method of treating a subject diagnosed with IBD, the method comprising administering a composition comprising a compound that modulates the activity of an IBD marker polypeptide and a pharmaceutically acceptable carrier, wherein the IBD marker is listed in Table 4 and expression of the IBD marker was modulated by rhIL-11 treatment in Table 4.

12. The method of claim 11, wherein the IBD marker is selected from the group consisting of HLA-DMβ

and RT1.DMβ

.

13. A method of treating a subject diagnosed with IBD, the method comprising administering a composition comprising an IBD marker polypeptide and a pharmaceutically acceptable carrier, wherein the IBD marker polypeptide is encoded by an IBD marker listed in Table 4 and expression of the IBD marker was increased by rhIL-11 treatment in Table 4.

14. A method of treating a subject diagnosed with IBD, the method comprising administering to the subject an isolated nucleic acid molecule encoding an IBD marker listed in Table 4 operably linked to at least one expression control sequence, wherein the IBD marker protein is expressed in the subject, and wherein expression of the IBD marker was increased by rhIL-11 treatment in Table 4.

15. A composition capable of inhibiting IBD in a subject, the composition comprising an IBD marker polypeptide and a pharmaceutically acceptable carrier, wherein the IBD marker polypeptide is encoded by an IBD marker listed in Table 4 and expression of the IBD marker was increased by rhIL-11 treatment in Table 4.

16. A composition capable of inhibiting IBD in a subject, the composition comprising a siRNA molecule and a pharmaceutically acceptable carrier, wherein the siRNA molecule is targeted to a mRNA corresponding to an IBD marker listed in Table 4 and expression of the IBD marker was decreased by rhIL-11 treatment in Table 4.

17. The method of claim 16, wherein the IBD marker is selected from the group consisting of HLA-DMβ

and RT1.DMβ

.

18. A method of treating a subject diagnosed with IBD, the method comprising providing to the subject a polynucleotide that inhibits expression of an IBD marker, wherein the IBD marker is listed in Table 4 and expression of the IBD marker was decreased by rhIL-11 treatment in Table 4.

19. A method of treating a subject diagnosed with IBD, the method comprising providing to the subject a siRNA molecule that inhibits expression of an IBD marker, wherein the siRNA molecule is targeted to a mRNA corresponding to an IBD marker listed in Table 4 and expression of the IBD marker was decreased by rhIL-11 treatment in Table 4.

20. A method of treating a subject diagnosed with IBD, the method comprising providing to the subject an antisense oligonucleotide complementary to an IBD marker, wherein the IBD marker is listed in Table 4 and expression of the IBD marker was decreased by rhIL-11 treatment in Table 4.

21. A method of treating a subject diagnosed with IBD, the method comprising providing to the subject an antibody capable of immunospecific binding to an IBD marker protein, wherein the IBD marker protein is encoded by an IBD marker listed in Table 4 and expression of the IBD marker was decreased by rhIL-11 treatment in Table 4.

22. A method of identifying a compound capable of increasing expression of an IBD marker selected from the group consisting of RegIII and Ins2 comprising the steps of:

(a) contacting a sample containing the IBD marker with one of a plurality of test compounds; and

(b) comparing the level of expression of the IBD marker in the contacted sample with that in a sample containing the IBD marker not contacted with the test compound,

wherein a substantial increase in the level of expression of the IBD marker in the contacted sample identifies the compound as useful in treating IBD.

23. A method of treating a subject diagnosed with IBD comprising administering to the subject a compound identified by the method of claim 22.

24. A method of identifying a test compound for inhibiting IBD comprising the step of comparing:

a) a level of expression of an IBD marker, wherein the IBD marker is listed in Tables 4 or 5, in a first sample, wherein the first sample is contacted with one of a plurality of test compound; and

b) a level of expression of the same IBD marker in a second sample, wherein the second sample is not contacted with the test compound,

wherein a substantially modulated level of expression of the IBD marker in the first sample, relative to the second sample, is an indication that the test compound is efficacious for inhibiting IBD.

25. The method of claim 24, wherein the IBD marker is selected from the group consisting of HLA-DMβ

and RT1.DMβ

, and wherein the substantially modulated level of expression is a substantially decreased level of expression.

26. The method of claim 24, wherein the IBD marker is selected from the group consisting of RegIII and Ins2, and wherein the substantially modulated level of expression is a substantially increased level of expression.