Methods for diagnosing and treating systemic lupus erythematosus disease and compositions thereof

• US 20030148298A1
• Filed: 04/03/2002
• Published: 08/07/2003
• Est. Priority Date: 04/03/2001
• Status: Abandoned Application

• Current Assignee: Gavin Bogle, Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: OʼʼToole, Margot, Legault, Holly
• Application Number:
  US10/115,717
• Publication Number:
  US 20030148298A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The present invention is directed to novel methods for diagnosis and prognosis of Systemic lupus erythematosus by identifying differentially expressed genes. Moreover, the present invention is also directed to methods that can be used to screen test compounds and therapies for the ability to inhibit systemic lupus erythematosus. Additionally, methods and molecule targets (genes and their products) for therapeutic intervention in systemic lupus erythematosus are described.

Claims

1. A method of diagnosing a subject with systemic lupus erythematosus, the method comprising the step of comparing:

a) a level of expression of a marker in a sample from the subject, wherein the marker is selected from the group consisting of markers listed in Tables 1 and 3-8, and

b) a normal level of expression of the marker in a control sample,

wherein a substantial difference between the level of expression of the marker in the sample from the subject and the normal level is an indication that the subject is afflicted with systemic lupus erythematosus.

2. The method of claim 1, wherein the marker corresponds to a transcribed polynucleotide or a portion thereof.

3. The method of claim 2, wherein the sample is collected from kidney tissue.

4. The method of claim 1, wherein the control sample is from a non-diseased subject and the substantial difference is a factor of at least about 2.

5. The method of claim 1, wherein the control sample is from non-involved tissue of the subject and the substantial difference is a factor of at least about 2.

6. The method of claim 1, wherein the control sample is from non-involved tissue of the subject and the substantial difference is a factor of at least about 5.

7. The method of claim 1, wherein the level of expression of the marker in the sample is assessed by detecting the presence in the sample of a protein corresponding to the marker.

8. The method of claim 7, wherein the presence of the protein is detected using a reagent which specifically binds with the protein.

9. The method of claim 8, wherein the reagent comprises an antibody or fragments thereof.

10. The method of claim 1, wherein the marker is selected from the markers listed in Tables 3-4.

11. The method of claim 1, wherein the marker is selected from the markers which are normalized by rapamycin as listed in Table 5.

12. The method of claim 1, wherein the marker is selected from the markers listed in Table 7.

13. The method of claim 1, wherein the marker is selected from the markers listed in Table 8.

14. The method of claim 1, wherein the level of expression of the marker in the sample is assessed by detecting the presence in the sample of a transcribed polynucleotide or portion thereof, wherein the transcribed polynucleotide comprises the marker.

15. The method of claim 14, wherein the transcribed polynucleotide is a mRNA.

16. The method of claim 14, wherein the transcribed polynucleotide is a cDNA.

17. The method of claim 1, wherein the level of expression of the marker in the sample is assessed by detecting the presence in the sample of a transcribed polynucleotide or a portion thereof which hybridizes with a labeled probe under stringent conditions, wherein the transcribed polynucleotide comprises the marker.

18. A method of diagnosing a subject with systemic lupus erythematosus, the method comprising the step of comparing:

a) a level of expression in a sample of the subject of each of a panel of markers independently selected from the markers listed in Tables 1 and 3-8, and

b) a normal level of expression of the panel of markers obtained from a control sample,

wherein the level of expression of the panel of markers is substantially different, relative to the corresponding normal level of expression of the panel of markers, indicates that the subject is afflicted with systemic lupus erythematosus.

19. The method of claim 18, wherein the panel of markers comprises at least 5 markers.

20. The method of claim 18, wherein the control sample is from a non-diseased subject.

21. The method of claim 18, wherein the control sample is from non-involved tissue of the subject.

22. The method of claim 18, wherein the panel of markers comprises markers listed in Table 8.

23. A method for monitoring the progression of systemic lupus erythematosus in a subject, the method comprising the steps of:

a) detecting in a subject sample at a first point in time, a level of expression of at least one marker, wherein the at least one marker is selected from the group consisting of markers listed in Tables 1 and 3-8;

b) repeating step a) at a subsequent point in time with the at least one marker;

c) detecting a substantial difference between the levels of expression detected in steps a) and b);

wherein the substantial difference between the levels of expression indicates that the subject has progressed to a different stage of systemic lupus erythematosus.

24. The method of claim 23, wherein at least 5 markers are selected from the group of markers listed in Tables and 3-8.

25. The method of claim 23, wherein the at least one marker corresponds to a transcribed polynucleotide or portion thereof.

26. The method of claim 25, wherein the samples are collected from kidney tissue.

27. A method of assessing the efficacy of a test compound for inhibiting systemic lupus erythematosus in a subject, the method comprising the step of comparing:

a) expression of a marker in a first sample obtained from the subject and exposed to the test compound, wherein the marker is selected from the group consisting of markers listed in Tables 1 and 3-8, and

b) expression of the same marker in a second sample obtained from the subject, wherein the second sample is not exposed to the test compound,

wherein a substantially different level of expression of the marker in the first sample, relative to the second sample, is an indication that the test compound is efficacious for inhibiting systemic lupus erythematosus in the subject.

28. The method of claim 27, wherein the first and second samples are portions of a single sample obtained from the subject.

29. The method of claim 28, wherein the level of expression in the first sample approximates the level of expression in a control sample.

30. A method of assessing the efficacy of a therapy for inhibiting systemic lupus erythematosus in a subject, the method comprising the steps of comparing:

a) expression of a marker in a first sample obtained from the subject prior to providing at least a portion of the therapy to the subject, wherein the marker is selected from the group consisting of markers listed in Tables 1 and 3-8, and

b) expression of the marker in a second sample following provision of the portion of the therapy,

wherein a substantially different level of expression of the marker in the second sample, relative to the first sample, is an indication that the test compound is efficacious for inhibiting systemic lupus erythematosus in the subject.

31. The method of claim 30, wherein a substantially similar level of expression in the second sample, relative to the control sample, is an additional indication that the test compound is efficacious for inhibiting systemic lupus erythematosus.

32. The method of claim 31, further comparing expression of the marker in a control sample, wherein expression of the marker in the second sample is similar to expression of the marker in the control sample.

33. A method of screening test compounds for inhibitors of systemic lupus erythematosus, the method comprising the steps of:

a) obtaining a sample comprising cells from the subject;

b) separately maintaining aliquots of the sample in the presence of a plurality of test compounds;

c) comparing the expression levels of a marker in each of the aliquots, wherein the marker is selected from the group consisting of markers listed in Tables 1 and 3-8; and

d) selecting one of the test compounds which induces a substantially different level of expression of the marker in the aliquot containing that test compound, relative to other test compounds.

34. The method of claim 33, wherein the substantially different level of expression is a substantially lower level of expression.

35. The method of claim 34, wherein the substantially different level of expression is a substantially enhanced level of expression.

36. A kit for diagnosing a subject with systemic lupus erythematosus, the kit comprising reagents for assessing expression of a marker selected from the group consisting of markers listed in Tables 1 and 3-8.

37. A kit for diagnosing systemic lupus erythematosus in a subject, the kit comprising a nucleic acid probe wherein the probe specifically binds with a transcribed polynucleotide corresponding to a marker selected from the group consisting of markers listed in Tables 1 and 3-8.

38. A kit for assessing the suitability of each of a plurality of compounds for inhibiting progression of systemic lupus erythematosus in a subject, the kit comprising:

a) the plurality of compounds; and

b) a reagent for assessing expression of a marker selected from the group consisting of markers listed in Tables 1 and 3-8.

39. A kit for diagnosing systemic lupus erythematosus in a subject, the kit comprising an antibody, wherein the antibody specifically binds with a protein corresponding to a marker selected from the group consisting of markers listed in Tables 1 and 3-8.

40. A method of modulating a level of expression of a marker selected from the markers listed in Tables 1 and 3-8, the method comprising providing to diseased cells of a subject an antisense oligonucleotide complementary to a polynucleotide corresponding to the marker.

41. A method of modulating a level of expression of a marker selected from the markers listed in Tables 1 and 3-8, the method comprising providing to diseased cells of a subject a protein.

42. The method of claim 41, wherein the protein is provided to the cells by providing a vector comprising a polynucleotide encoding the protein to the cells.

43. A method of modulating a level of expression of a marker selected from the markers listed in Tables 1 and 3-8, the method comprising providing to diseased cells of a subject an antibody.

44. The method according to claim 43, wherein the method further comprises a therapeutic moiety conjugated to the antibody.

45. The method according to claim 43, wherein the method further comprises providing to the diseased cells an additional antibody.

46. A method of localizing a therapeutic moiety to diseased tissue comprising exposing the tissue to an antibody which is specific to a protein encoded from a marker listed in Tables 1 and 3-8.

47. A method of localizing a therapeutic moiety to diseased tissue comprising exposing the tissue to a plurality of antibodies which are each specific to a protein encoded from a marker listed in Tables 1 and 3-8.

48. A method of screening for a test compound capable of modulating the activity of a protein encoded from a marker listed in Tables 1 and 3-8, the method comprising combining the protein and the test compound, and determining the effect of the test compound on the therapeutic efficacy of the protein.

51. The antibody of claim 48, wherein the antibody is a monoclonal antibody.

54. A composition comprising the peptide of claim 51.

49. A method of screening for a bioactive agent capable of interfering with the binding of a protein encoded from a marker listed in Tables 1 and 3-8 and an antibody which binds to the protein, the method comprising:

a) combining the protein, a bioactive agent and an antibody which binds to the protein; and

b) determining the binding of the protein or fragment thereof and the antibody.

52. The antibody of claim 49, wherein the antibody is a humanized antibody.

50. An antibody which specifically binds to a protein encoded from a marker listed in Tables 1 and 3-8.

53. A peptide encoded from markers listed in Tables 1 and 3-8.

55. A composition capable of modulating an immune response in a subject, the composition comprising a protein encoded from a marker listed in Tables 1 and 3-8, and a pharmaceutically acceptable carrier.

56. A biochip comprising a panel of markers selected from the group of markers listed in Tables 1 and 3-8.

57. The biochip of claim 56, wherein the markers are selected for subjects suspected of having systemic lupus nephritis, wherein the subjects display signs nephritis.

58. The biochip of claim 56, wherein the markers are selected for subjects suspected of having systemic lupus nephritis, wherein the subjects display signs of facial lesions.